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Zhang K, Wang L, Gao W, Guo R. Retinol-binding protein 4 in skeletal and cardiac muscle: molecular mechanisms, clinical implications, and future perspectives. Front Cell Dev Biol 2025; 13:1587165. [PMID: 40276651 PMCID: PMC12018443 DOI: 10.3389/fcell.2025.1587165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Accepted: 03/24/2025] [Indexed: 04/26/2025] Open
Abstract
Retinol-binding protein 4 (RBP4) has emerged as a critical adipokine involved in the pathophysiology of metabolic and cardiovascular diseases. Beyond its classical role in retinol transport, RBP4 influences insulin resistance, inflammation, lipid metabolism, mitochondrial function, and cellular apoptosis in both skeletal and cardiac muscles. Elevated levels of RBP4 are associated with obesity, type 2 mellitus diabetes, and cardiovascular diseases, making it a potential biomarker and therapeutic target. This comprehensive review elucidates the molecular mechanisms by which RBP4 affects skeletal and cardiac muscle physiology. We discuss its clinical implications as a biomarker for disease risk and progression, explore therapeutic strategies targeting RBP4, and highlight future research directions. Understanding the multifaceted roles of RBP4 could pave the way for novel interventions against metabolic and cardiovascular disorders.
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Affiliation(s)
- Kangzhen Zhang
- Department of Geriatrics, Nanjing Central Hospital, Nanjing, China
| | - Lijuan Wang
- Department of General Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Wei Gao
- Department of Geriatrics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Rong Guo
- Department of Cardiology, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China
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2
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Qi H, Zhou Y, Hou HT, Wei JH, He GW, Yang Q. Contributing role and molecular basis of Vitamin D/Vitamin D receptor deficiency in hyperhomocysteinemia-induced cardiac hypertrophy. Biochem Pharmacol 2025; 234:116812. [PMID: 39978691 DOI: 10.1016/j.bcp.2025.116812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 01/11/2025] [Accepted: 02/17/2025] [Indexed: 02/22/2025]
Abstract
Hyperhomocysteinemia and vitamin D deficiency are known to promote cardiac hypertrophy, however, whether vitamin D signaling is involved in hyperhomocysteinemia-induced cardiac hypertrophy remains unexplored. This study aimed to address this question by clarifying the effect of homocysteine on vitamin D and vitamin D receptor (VDR), with further elucidation of the regulatory mechanisms. Methionine diet-induced hyperhomocysteinemic (HHcy) rats and homocysteine-incubated cardiomyocytes were used as in vivo and in vitro models of cardiac hypertrophy. Gain-and-loss-of function of VDR and miR-125b-5p were achieved by plasmid transfection and AAV9-mediated delivery. HHcy rats showed lowered serum and cardiac 1,25(OH)2D3 levels and increased 24-hydroxylase (CYP24A1) expression in kidney and myocardium. VDR expression was downregulated and miR-125b-5p was upregulated in the myocardium of HHcy rats and in homocysteine-incubated cardiomyocytes as well. Knockdown of VDR facilitated while overexpression mitigated homocysteine-induced cardiomyocyte hypertrophy, accompanied by activation and inhibition of calcineurin/nuclear factor of activated T cells 4 (NFATc4) respectively. Dual-luciferase reporter gene assay and gain-and-loss-of function of miR-125b-5p in cardiomyocytes indicated the targeting and repressing of VDR by miR-125b-5p and its pro-hypertrophic effect. The role of miR-125b-5p-mediated VDR downregulation in homocysteine-induced cardiac hypertrophy was further demonstrated in vivo. Treatment with VDR agonist inhibited hypertrophic growth both in vivo and in vitro, resulting from VDR upregulation and consequent calcineurin/NFATc4 inhibition. These findings demonstrated that homocysteine reduces 1,25(OH)2D3 level in both plasma and myocardium via upregulating CYP24A1 and represses myocardial VDR expression via the mediation of miR-125b-5p. Vitamin D/VDR deficiency contributes to hyperhomocysteinemia-induced cardiac hypertrophy via activating calcineurin/NFATc4 pathway.
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Affiliation(s)
- Hang Qi
- Institute of Cardiovascular Diseases & Department of Cardiac Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College & Tianjin University, Tianjin 300457, China; Tianjin Key Laboratory of Molecular Regulation of Cardiovascular Diseases and Translational Medicine, Tianjin 300457, China
| | - Yang Zhou
- Institute of Cardiovascular Diseases & Department of Cardiac Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College & Tianjin University, Tianjin 300457, China; Tianjin Key Laboratory of Molecular Regulation of Cardiovascular Diseases and Translational Medicine, Tianjin 300457, China
| | - Hai-Tao Hou
- Institute of Cardiovascular Diseases & Department of Cardiac Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College & Tianjin University, Tianjin 300457, China; Tianjin Key Laboratory of Molecular Regulation of Cardiovascular Diseases and Translational Medicine, Tianjin 300457, China
| | - Jia-Hui Wei
- Institute of Cardiovascular Diseases & Department of Cardiac Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College & Tianjin University, Tianjin 300457, China; Tianjin Key Laboratory of Molecular Regulation of Cardiovascular Diseases and Translational Medicine, Tianjin 300457, China
| | - Guo-Wei He
- Institute of Cardiovascular Diseases & Department of Cardiac Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College & Tianjin University, Tianjin 300457, China; Tianjin Key Laboratory of Molecular Regulation of Cardiovascular Diseases and Translational Medicine, Tianjin 300457, China
| | - Qin Yang
- Institute of Cardiovascular Diseases & Department of Cardiac Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College & Tianjin University, Tianjin 300457, China; Tianjin Key Laboratory of Molecular Regulation of Cardiovascular Diseases and Translational Medicine, Tianjin 300457, China.
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Kaplan A, El‐Samadi L, Zahreddine R, Amin G, Booz GW, Zouein FA. Canonical or non-canonical, all aspects of G protein-coupled receptor kinase 2 in heart failure. Acta Physiol (Oxf) 2025; 241:e70010. [PMID: 39960030 PMCID: PMC11831727 DOI: 10.1111/apha.70010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 01/12/2025] [Accepted: 01/20/2025] [Indexed: 02/20/2025]
Abstract
G protein-coupled receptor kinase 2 (GRK2) with its multidomain structure performs various crucial cellular functions under both normal and pathological conditions. Overexpression of GRK2 is linked to cardiovascular diseases, and its inhibition or deletion has been shown to be protective. The functions of GRK2 extend beyond G protein-coupled receptor (GPCR) signaling, influencing non-GPCR substrates as well. Increased GRK2 in heart failure (HF) initially may be protective but ultimately leads to maladaptive effects such as GPCR desensitization, insulin resistance, and apoptosis. The multifunctional nature of GRK2, including its action in hypertrophic gene expression, insulin signaling, and cardiac fibrosis, highlights its complex role in HF pathogenesis. Additionally, GRK2 is involved in mitochondrial biogenesis and lipid metabolism. GRK2 also regulates epinephrine secretion from the adrenal gland and its increase in circulating lymphocytes can be used to monitor HF status. Overall, GRK2 is a multifaceted protein with significant implications for HF and the regulation of GRK2 is crucial for understanding and treating cardiovascular diseases.
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Affiliation(s)
- Abdullah Kaplan
- Department of Pharmacology and ToxicologyAmerican University of Beirut Faculty of MedicineBeirutLebanon
- The Cardiovascular, Renal, and Metabolic Diseases Research Center of ExcellenceAmerican University of Beirut Medical CenterBeirutLebanon
- Cardiology ClinicKemer Public HospitalAntalyaTurkey
| | - Lana El‐Samadi
- Department of Pharmacology and ToxicologyAmerican University of Beirut Faculty of MedicineBeirutLebanon
- The Cardiovascular, Renal, and Metabolic Diseases Research Center of ExcellenceAmerican University of Beirut Medical CenterBeirutLebanon
| | - Rana Zahreddine
- Department of Pharmacology and ToxicologyAmerican University of Beirut Faculty of MedicineBeirutLebanon
- The Cardiovascular, Renal, and Metabolic Diseases Research Center of ExcellenceAmerican University of Beirut Medical CenterBeirutLebanon
| | - Ghadir Amin
- Department of Pharmacology and ToxicologyAmerican University of Beirut Faculty of MedicineBeirutLebanon
- The Cardiovascular, Renal, and Metabolic Diseases Research Center of ExcellenceAmerican University of Beirut Medical CenterBeirutLebanon
- Department of Pharmacology and Toxicology, School of MedicineUniversity of Mississippi Medical CenterJacksonMississippiUSA
| | - George W. Booz
- Department of Pharmacology and Toxicology, School of MedicineUniversity of Mississippi Medical CenterJacksonMississippiUSA
| | - Fouad A. Zouein
- Department of Pharmacology and ToxicologyAmerican University of Beirut Faculty of MedicineBeirutLebanon
- The Cardiovascular, Renal, and Metabolic Diseases Research Center of ExcellenceAmerican University of Beirut Medical CenterBeirutLebanon
- Department of Pharmacology and Toxicology, School of MedicineUniversity of Mississippi Medical CenterJacksonMississippiUSA
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Gladka MM, Kohela A, de Leeuw AE, Molenaar B, Versteeg D, Kooijman L, van Geldorp M, van Ham WB, Caliandro R, Haigh JJ, van Veen TAB, van Rooij E. Hypoxia-responsive zinc finger E-box-binding homeobox 2 (ZEB2) regulates a network of calcium-handling genes in the injured heart. Cardiovasc Res 2024; 120:1869-1883. [PMID: 39308239 PMCID: PMC11630050 DOI: 10.1093/cvr/cvae163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 04/16/2024] [Accepted: 05/11/2024] [Indexed: 12/11/2024] Open
Abstract
AIMS Intracellular calcium (Ca2+) overload is known to play a critical role in the development of cardiac dysfunction. Despite the remarkable improvement in managing the progression of heart disease, developing effective therapies for heart failure (HF) remains a challenge. A better understanding of molecular mechanisms that maintain proper Ca2+ levels and contractility in the injured heart could be of therapeutic value. METHODS AND RESULTS Here, we report that transcription factor zinc finger E-box-binding homeobox 2 (ZEB2) is induced by hypoxia-inducible factor 1-alpha (HIF1α) in hypoxic cardiomyocytes and regulates a network of genes involved in Ca2+ handling and contractility during ischaemic heart disease. Gain- and loss-of-function studies in genetic mouse models revealed that ZEB2 expression in cardiomyocytes is necessary and sufficient to protect the heart against ischaemia-induced diastolic dysfunction and structural remodelling. Moreover, RNA sequencing of ZEB2-overexpressing (Zeb2 cTg) hearts post-injury implicated ZEB2 in regulating numerous Ca2+-handling and contractility-related genes. Mechanistically, ZEB2 overexpression increased the phosphorylation of phospholamban at both serine-16 and threonine-17, implying enhanced activity of sarcoplasmic reticulum Ca2+-ATPase (SERCA2a), thereby augmenting SR Ca2+ uptake and contractility. Furthermore, we observed a decrease in the activity of Ca2+-dependent calcineurin/NFAT signalling in Zeb2 cTg hearts, which is the main driver of pathological cardiac remodelling. On a post-transcriptional level, we showed that ZEB2 expression can be regulated by the cardiomyocyte-specific microRNA-208a (miR-208a). Blocking the function of miR-208a with anti-miR-208a increased ZEB2 expression in the heart and effectively protected from the development of pathological cardiac hypertrophy. CONCLUSION Together, we present ZEB2 as a central regulator of contractility and Ca2+-handling components in the mammalian heart. Further mechanistic understanding of the role of ZEB2 in regulating Ca2+ homeostasis in cardiomyocytes is an essential step towards the development of improved therapies for HF.
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Affiliation(s)
- Monika M Gladka
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Centre Utrecht (UMCU), Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
- Department of Medical Biology, Amsterdam University Medical Center, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands
| | - Arwa Kohela
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Centre Utrecht (UMCU), Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
- School of Biotechnology, Nile University, Giza, Egypt
| | - Anne E de Leeuw
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Centre Utrecht (UMCU), Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
| | - Bas Molenaar
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Centre Utrecht (UMCU), Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
| | - Danielle Versteeg
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Centre Utrecht (UMCU), Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
| | - Lieneke Kooijman
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Centre Utrecht (UMCU), Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
| | - Mariska van Geldorp
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Centre Utrecht (UMCU), Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
| | - Willem B van Ham
- Department of Medical Physiology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Rocco Caliandro
- Department of Medical Biology, Amsterdam University Medical Center, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands
| | - Jody J Haigh
- Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Canada
| | - Toon A B van Veen
- Department of Medical Physiology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Eva van Rooij
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Centre Utrecht (UMCU), Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
- Department of Cardiology, University Medical Centre Utrecht (UMCU), Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
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Boda VK, Yasmen N, Jiang J, Li W. Pathophysiological significance and modulation of the transient receptor potential canonical 3 ion channel. Med Res Rev 2024; 44:2510-2544. [PMID: 38715347 PMCID: PMC11452291 DOI: 10.1002/med.22048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 04/11/2024] [Accepted: 04/23/2024] [Indexed: 05/12/2024]
Abstract
Transient receptor potential canonical 3 (TRPC3) protein belongs to the TRP family of nonselective cation channels. Its activation occurs by signaling through a G protein-coupled receptor (GPCR) and a phospholipase C-dependent (PLC) pathway. Perturbations in the expression of TRPC3 are associated with a plethora of pathophysiological conditions responsible for disorders of the cardiovascular, immune, and central nervous systems. The recently solved cryo-EM structure of TRPC3 provides detailed inputs about the underlying mechanistic aspects of the channel, which in turn enables more efficient ways of designing small-molecule modulators. Pharmacologically targeting TRPC3 in animal models has demonstrated great efficacy in treating diseases including cancers, neurological disorders, and cardiovascular diseases. Despite extensive scientific evidence supporting some strong correlations between the expression and activity of TRPC3 and various pathophysiological conditions, therapeutic strategies based on its pharmacological modulations have not led to clinical trials. The development of small-molecule TRPC3 modulators with high safety, sufficient brain penetration, and acceptable drug-like profiles remains in progress. Determining the pathological mechanisms for TRPC3 involvement in human diseases and understanding the requirements for a drug-like TRPC3 modulator will be valuable in advancing small-molecule therapeutics to future clinical trials. In this review, we provide an overview of the origin and activation mechanism of TRPC3 channels, diseases associated with irregularities in their expression, and new development in small-molecule modulators as potential therapeutic interventions for treating TRPC3 channelopathies.
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Affiliation(s)
- Vijay K. Boda
- Department of Pharmaceutical Sciences, and Drug Discovery Center, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA
| | - Nelufar Yasmen
- Department of Pharmaceutical Sciences, and Drug Discovery Center, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA
| | - Jianxiong Jiang
- Department of Pharmaceutical Sciences, and Drug Discovery Center, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA
| | - Wei Li
- Department of Pharmaceutical Sciences, and Drug Discovery Center, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA
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Song S, Xie L, Xu H, Xu K, Fu H, Zhang L, Hou R, Tao Y, Guo Y. Evaluation of cardiac remodeling in pediatric chronic kidney disease by cardiovascular magnetic resonance. BMC Cardiovasc Disord 2024; 24:526. [PMID: 39354376 PMCID: PMC11443670 DOI: 10.1186/s12872-024-04179-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 09/10/2024] [Indexed: 10/03/2024] Open
Abstract
BACKGROUND Children with chronic kidney disease (CKD) are at high risk of cardiovascular disease. Cardiovascular magnetic resonance (CMR) is the reference method for assessing cardiac remodeling. To our knowledge, no study has reported a comprehensive analysis of left ventricular(LV) cardiac remodeling using CMR in different stages of pediatric CKD. This prospective case-control study aimed to investigate cardiac remodeling in pediatric CKD, using CMR, and determine its relationship with risk factors. METHOD CMR was performed in 124 children with CKD and 50 controls. The cardiac remodeling parameters included left ventricular mass index (LVMI), LV remodeling index (LVRI), and LV wall thickness. Univariable and multivariable analyses were performed to assess the cardiac remodeling risk factors. RESULTS Cardiac remodeling was observed in 35.5% (44/124) of children with CKD. The LVMI, LVRI, and LV wall thickness were higher in advanced stages of CKD (P < 0.05). In the CKD stage 1-2 group, a lower in the estimated glomerular filtration rate was an independent determinant of impaired LVMI (β = -0.425, P = 0.019) and LVRI (β = -0.319, P = 0.044). A higher protein to creatinine ratio(PCR) was independently associated with impaired LVRI (β = 0.429, P = 0.022). In the CKD stage 3-5 group, higher in systolic blood pressure (SBP) (β = 0.464, P = 0.005) and PCR (β = 0.852, P = 0.031) were independent determinants of impaired LVMI. Additionally, higher SBP was positively correlated with impaired LVRI(r = 0.599, P < 0.001). There was a trend toward more abnormal cardiac remodeling in the CKD stage 3-5 group with hypertension than those without. CONCLUSION Cardiac remodeling is prevalent in children with CKD, from an early stage. kidney markers are independently associated with cardiac remodeling. Hypertension increases the risk of cardiac remodeling in CKD stages 3-5. Strict BP control may help reverse or prevent remodeling.
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Affiliation(s)
- Sisi Song
- Department of Radiology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, (Sichuan University), Ministry of Education, Chengdu, China
- Department of Radiology, Deyang People's Hospital, Deyang, Sichuan, China
| | - Linjun Xie
- Department of Radiology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, (Sichuan University), Ministry of Education, Chengdu, China
| | - Huayan Xu
- Department of Radiology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, (Sichuan University), Ministry of Education, Chengdu, China
| | - Ke Xu
- Department of Radiology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, (Sichuan University), Ministry of Education, Chengdu, China
| | - Hang Fu
- Department of Radiology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, (Sichuan University), Ministry of Education, Chengdu, China
| | - Lu Zhang
- Department of Radiology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, (Sichuan University), Ministry of Education, Chengdu, China
| | - Ruilai Hou
- Department of Radiology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, (Sichuan University), Ministry of Education, Chengdu, China
- Department of Radiology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yuhong Tao
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, (Sichuan University), Ministry of Education, Chengdu, China.
- Division of Nephrology, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.
| | - Yingkun Guo
- Department of Radiology, West China Second University Hospital, Sichuan University, Chengdu, China.
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, (Sichuan University), Ministry of Education, Chengdu, China.
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Dondi C, Vogler G, Gupta A, Walls SM, Kervadec A, Marchant J, Romero MR, Diop S, Goode J, Thomas JB, Colas AR, Bodmer R, Montminy M, Ocorr K. The nutrient sensor CRTC and Sarcalumenin/thinman represent an alternate pathway in cardiac hypertrophy. Cell Rep 2024; 43:114549. [PMID: 39093699 PMCID: PMC11402474 DOI: 10.1016/j.celrep.2024.114549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 05/06/2024] [Accepted: 07/12/2024] [Indexed: 08/04/2024] Open
Abstract
CREB-regulated transcription co-activator (CRTC) is activated by Calcineurin (CaN) to regulate gluconeogenic genes. CaN also has roles in cardiac hypertrophy. Here, we explore a cardiac-autonomous role for CRTC in cardiac hypertrophy. In Drosophila, CRTC mutants exhibit severe cardiac restriction, myofibrillar disorganization, fibrosis, and tachycardia. Cardiac-specific CRTC knockdown (KD) phenocopies mutants, and cardiac overexpression causes hypertrophy. CaN-induced hypertrophy in Drosophila is reduced in CRTC mutants, suggesting that CRTC mediates the effects. RNA sequencing (RNA-seq) of CRTC-KD and -overexpressing hearts reveals contraregulation of metabolic genes. Genes with conserved CREB sites include the fly ortholog of Sarcalumenin, a Ca2+-binding protein. Cardiac manipulation of this gene recapitulates the CRTC-KD and -overexpression phenotypes. CRTC KD in zebrafish also causes cardiac restriction, and CRTC KD in human induced cardiomyocytes causes a reduction in Srl expression and increased action potential duration. Our data from three model systems suggest that CaN-CRTC-Sarcalumenin signaling represents an alternate, conserved pathway underlying cardiac function and hypertrophy.
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Affiliation(s)
- Cristiana Dondi
- Development, Aging and Regeneration Program, Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Georg Vogler
- Development, Aging and Regeneration Program, Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Anjali Gupta
- Development, Aging and Regeneration Program, Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Stanley M Walls
- Development, Aging and Regeneration Program, Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Anaïs Kervadec
- Development, Aging and Regeneration Program, Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - James Marchant
- Development, Aging and Regeneration Program, Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Michaela R Romero
- Development, Aging and Regeneration Program, Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Soda Diop
- Development, Aging and Regeneration Program, Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Jason Goode
- Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - John B Thomas
- Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Alex R Colas
- Development, Aging and Regeneration Program, Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Rolf Bodmer
- Development, Aging and Regeneration Program, Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Marc Montminy
- Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Karen Ocorr
- Development, Aging and Regeneration Program, Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
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Hinton A, Claypool SM, Neikirk K, Senoo N, Wanjalla CN, Kirabo A, Williams CR. Mitochondrial Structure and Function in Human Heart Failure. Circ Res 2024; 135:372-396. [PMID: 38963864 PMCID: PMC11225798 DOI: 10.1161/circresaha.124.323800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/06/2024]
Abstract
Despite clinical and scientific advancements, heart failure is the major cause of morbidity and mortality worldwide. Both mitochondrial dysfunction and inflammation contribute to the development and progression of heart failure. Although inflammation is crucial to reparative healing following acute cardiomyocyte injury, chronic inflammation damages the heart, impairs function, and decreases cardiac output. Mitochondria, which comprise one third of cardiomyocyte volume, may prove a potential therapeutic target for heart failure. Known primarily for energy production, mitochondria are also involved in other processes including calcium homeostasis and the regulation of cellular apoptosis. Mitochondrial function is closely related to morphology, which alters through mitochondrial dynamics, thus ensuring that the energy needs of the cell are met. However, in heart failure, changes in substrate use lead to mitochondrial dysfunction and impaired myocyte function. This review discusses mitochondrial and cristae dynamics, including the role of the mitochondria contact site and cristae organizing system complex in mitochondrial ultrastructure changes. Additionally, this review covers the role of mitochondria-endoplasmic reticulum contact sites, mitochondrial communication via nanotunnels, and altered metabolite production during heart failure. We highlight these often-neglected factors and promising clinical mitochondrial targets for heart failure.
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Affiliation(s)
- Antentor Hinton
- Department of Molecular Physiology and Biophysics (A.H., K.N.), Vanderbilt University Medical Center, Nashville
| | - Steven M. Claypool
- Department of Physiology, Mitochondrial Phospholipid Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (S.M.C., N.S.)
| | - Kit Neikirk
- Department of Molecular Physiology and Biophysics (A.H., K.N.), Vanderbilt University Medical Center, Nashville
| | - Nanami Senoo
- Department of Physiology, Mitochondrial Phospholipid Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (S.M.C., N.S.)
| | - Celestine N. Wanjalla
- Department of Medicine, Division of Clinical Pharmacology (C.N.W., A.K.), Vanderbilt University Medical Center, Nashville
| | - Annet Kirabo
- Department of Medicine, Division of Clinical Pharmacology (C.N.W., A.K.), Vanderbilt University Medical Center, Nashville
- Vanderbilt Center for Immunobiology (A.K.)
- Vanderbilt Institute for Infection, Immunology and Inflammation (A.K.)
- Vanderbilt Institute for Global Health (A.K.)
| | - Clintoria R. Williams
- Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, OH (C.R.W.)
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Godoy Coto J, Pereyra EV, Cavalli FA, Valverde CA, Caldiz CI, Maté SM, Yeves AM, Ennis IL. Exercise-induced cardiac mitochondrial reorganization and enhancement in spontaneously hypertensive rats. Pflugers Arch 2024; 476:1109-1123. [PMID: 38625371 DOI: 10.1007/s00424-024-02956-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 03/22/2024] [Accepted: 03/28/2024] [Indexed: 04/17/2024]
Abstract
The myocardium is a highly oxidative tissue in which mitochondria are essential to supply the energy required to maintain pump function. When pathological hypertrophy develops, energy consumption augments and jeopardizes mitochondrial capacity. We explored the cardiac consequences of chronic swimming training, focusing on the mitochondrial network, in spontaneously hypertensive rats (SHR). Male adult SHR were randomized to sedentary or trained (T: 8-week swimming protocol). Blood pressure and echocardiograms were recorded, and hearts were removed at the end of the training period to perform molecular, imaging, or isolated mitochondria studies. Swimming improved cardiac midventricular shortening and decreased the pathological hypertrophic marker atrial natriuretic peptide. Oxidative stress was reduced, and even more interesting, mitochondrial spatial distribution, dynamics, function, and ATP were significantly improved in the myocardium of T rats. In the signaling pathway triggered by training, we detected an increase in the phosphorylation level of both AKT and glycogen synthase kinase-3 β, key downstream targets of insulin-like growth factor 1 signaling that are crucially involved in mitochondria biogenesis and integrity. Aerobic exercise training emerges as an effective approach to improve pathological cardiac hypertrophy and bioenergetics in hypertension-induced cardiac hypertrophy.
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Affiliation(s)
- Joshua Godoy Coto
- Centro de Investigaciones Cardiovasculares "Dr. Horacio E. Cingolani", Facultad de Ciencias Médicas, Universidad Nacional de La Plata (UNLP) - CONICET, La Plata, Argentina
| | - Erica V Pereyra
- Centro de Investigaciones Cardiovasculares "Dr. Horacio E. Cingolani", Facultad de Ciencias Médicas, Universidad Nacional de La Plata (UNLP) - CONICET, La Plata, Argentina
| | - Fiorella A Cavalli
- Centro de Investigaciones Cardiovasculares "Dr. Horacio E. Cingolani", Facultad de Ciencias Médicas, Universidad Nacional de La Plata (UNLP) - CONICET, La Plata, Argentina
| | - Carlos A Valverde
- Centro de Investigaciones Cardiovasculares "Dr. Horacio E. Cingolani", Facultad de Ciencias Médicas, Universidad Nacional de La Plata (UNLP) - CONICET, La Plata, Argentina
| | - Claudia I Caldiz
- Centro de Investigaciones Cardiovasculares "Dr. Horacio E. Cingolani", Facultad de Ciencias Médicas, Universidad Nacional de La Plata (UNLP) - CONICET, La Plata, Argentina
| | - Sabina M Maté
- Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner" - Facultad de Ciencias Médicas, Universidad Nacional de La Plata (UNLP) - CONICET, La Plata, Argentina
| | - Alejandra M Yeves
- Centro de Investigaciones Cardiovasculares "Dr. Horacio E. Cingolani", Facultad de Ciencias Médicas, Universidad Nacional de La Plata (UNLP) - CONICET, La Plata, Argentina.
| | - Irene L Ennis
- Centro de Investigaciones Cardiovasculares "Dr. Horacio E. Cingolani", Facultad de Ciencias Médicas, Universidad Nacional de La Plata (UNLP) - CONICET, La Plata, Argentina.
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10
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Gao Y, Li S, Liu X, Si D, Chen W, Yang F, Sun H, Yang P. RyR2 Stabilizer Attenuates Cardiac Hypertrophy by Downregulating TNF-α/NF-κB/NLRP3 Signaling Pathway through Inhibiting Calcineurin. J Cardiovasc Transl Res 2024; 17:481-495. [PMID: 38652413 DOI: 10.1007/s12265-023-10376-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 03/13/2023] [Indexed: 04/25/2024]
Abstract
The effect of Ryanodine receptor2 (RyR2) and its stabilizer on cardiac hypertrophy is not well known. C57/BL6 mice underwent transverse aortic contraction (TAC) or sham surgery were administered dantrolene, the RyR2 stabilizer, or control drug. Dantrolene significantly alleviated TAC-induced cardiac hypertrophy in mice, and RNA sequencing was performed implying calcineurin/NFAT3 and TNF-α/NF-κB/NLRP3 as critical signaling pathways. Further expression analysis and Western blot with heart tissue as well as neonatal rat cardiomyocyte (NRCM) model confirmed dantrolene decreases the activation of calcineurin/NFAT3 signaling pathway and TNF-α/NF-κB/NLRP3 signaling pathway, which was similar to FK506 and might be attenuated by calcineurin overexpression. The present study shows for the first time that RyR2 stabilizer dantrolene attenuates cardiac hypertrophy by inhibiting the calcineurin, therefore downregulating the TNF-α/NF-κB/NLRP3 pathway.
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MESH Headings
- Animals
- Signal Transduction/drug effects
- Tumor Necrosis Factor-alpha/metabolism
- Ryanodine Receptor Calcium Release Channel/metabolism
- Ryanodine Receptor Calcium Release Channel/genetics
- Ryanodine Receptor Calcium Release Channel/drug effects
- Calcineurin/metabolism
- NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
- Mice, Inbred C57BL
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/pathology
- Disease Models, Animal
- NF-kappa B/metabolism
- Down-Regulation
- Dantrolene/pharmacology
- Male
- Calcineurin Inhibitors/pharmacology
- NFATC Transcription Factors/metabolism
- Cells, Cultured
- Cardiomegaly/metabolism
- Cardiomegaly/prevention & control
- Cardiomegaly/pathology
- Cardiomegaly/drug therapy
- Rats, Sprague-Dawley
- Rats
- Hypertrophy, Left Ventricular/prevention & control
- Hypertrophy, Left Ventricular/metabolism
- Hypertrophy, Left Ventricular/pathology
- Hypertrophy, Left Ventricular/physiopathology
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Affiliation(s)
- Yi Gao
- Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, China
- Jilin Provincial International Joint Research Center of Cardiovascular Disease Precision Medicine, Changchun, China
- Jilin Provincial Precision Medicine Key Laboratory for Cardiovascular Genetic Diagnosis, Changchun, China
| | - Shuai Li
- Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Xueyan Liu
- Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, China
- Jilin Provincial International Joint Research Center of Cardiovascular Disease Precision Medicine, Changchun, China
- Jilin Provincial Precision Medicine Key Laboratory for Cardiovascular Genetic Diagnosis, Changchun, China
| | - Daoyuan Si
- Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, China
- Jilin Provincial International Joint Research Center of Cardiovascular Disease Precision Medicine, Changchun, China
- Jilin Provincial Precision Medicine Key Laboratory for Cardiovascular Genetic Diagnosis, Changchun, China
| | - Weiwei Chen
- Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, China
- Jilin Provincial International Joint Research Center of Cardiovascular Disease Precision Medicine, Changchun, China
- Jilin Provincial Precision Medicine Key Laboratory for Cardiovascular Genetic Diagnosis, Changchun, China
| | - Fenghua Yang
- Guangdong Laboratory Animals Monitoring Institute, Guangzhou, China
| | - Huan Sun
- Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, China.
- Jilin Provincial International Joint Research Center of Cardiovascular Disease Precision Medicine, Changchun, China.
- Jilin Provincial Precision Medicine Key Laboratory for Cardiovascular Genetic Diagnosis, Changchun, China.
| | - Ping Yang
- Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, China.
- Jilin Provincial International Joint Research Center of Cardiovascular Disease Precision Medicine, Changchun, China.
- Jilin Provincial Precision Medicine Key Laboratory for Cardiovascular Genetic Diagnosis, Changchun, China.
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11
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Eid RA. Acylated ghrelin protection inhibits apoptosis in the remote myocardium post-myocardial infarction by inhibiting calcineurin and activating ARC. Arch Physiol Biochem 2024; 130:215-229. [PMID: 34965150 DOI: 10.1080/13813455.2021.2017463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 12/07/2021] [Indexed: 10/19/2022]
Abstract
This study investigated if acylated ghrelin (AG) could inhibit myocardial infarction (MI)-induced apoptosis in the left ventricles (LV) of male rats and tested if this protection involves modulating ARC anti-apoptotic protein. Rats (n = 12/group) were assigned as a sham-operated, a sham + AG (100 µg/kg, 2x/d, S.C.), MI, and MI + AG. With no antioxidant activity or expression of FAS, AG inhibited caspase-3, 8, and 9 and decreased cytosolic/mitochondrial levels of cytochrome-c, Bax, Bad, and Bad-BCL-2 complex in the LVs of the sham-operated and MI-treated rats. Concomitantly, AG preserved the mitochondria structure, decreased mtPTP, and enhanced state-3 respiration in the LVs of both treated groups. These effects were associated with increased mitochondrial levels of ARC and a reduction in the activity of calcineurin. Overall, AG suppresses MI-induced ventricular apoptosis by inhibition of calcineurin, activation of ARC, and preserving mitochondria integrity.
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Affiliation(s)
- Refaat A Eid
- Department of Pathology, College of Medicine, King Khalid University, Abha, Saudi Arabia
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12
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Jolfayi AG, Kohansal E, Ghasemi S, Naderi N, Hesami M, MozafaryBazargany M, Moghadam MH, Fazelifar AF, Maleki M, Kalayinia S. Exploring TTN variants as genetic insights into cardiomyopathy pathogenesis and potential emerging clues to molecular mechanisms in cardiomyopathies. Sci Rep 2024; 14:5313. [PMID: 38438525 PMCID: PMC10912352 DOI: 10.1038/s41598-024-56154-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 03/01/2024] [Indexed: 03/06/2024] Open
Abstract
The giant protein titin (TTN) is a sarcomeric protein that forms the myofibrillar backbone for the components of the contractile machinery which plays a crucial role in muscle disorders and cardiomyopathies. Diagnosing TTN pathogenic variants has important implications for patient management and genetic counseling. Genetic testing for TTN variants can help identify individuals at risk for developing cardiomyopathies, allowing for early intervention and personalized treatment strategies. Furthermore, identifying TTN variants can inform prognosis and guide therapeutic decisions. Deciphering the intricate genotype-phenotype correlations between TTN variants and their pathologic traits in cardiomyopathies is imperative for gene-based diagnosis, risk assessment, and personalized clinical management. With the increasing use of next-generation sequencing (NGS), a high number of variants in the TTN gene have been detected in patients with cardiomyopathies. However, not all TTN variants detected in cardiomyopathy cohorts can be assumed to be disease-causing. The interpretation of TTN variants remains challenging due to high background population variation. This narrative review aimed to comprehensively summarize current evidence on TTN variants identified in published cardiomyopathy studies and determine which specific variants are likely pathogenic contributors to cardiomyopathy development.
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Affiliation(s)
- Amir Ghaffari Jolfayi
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Erfan Kohansal
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Serwa Ghasemi
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Niloofar Naderi
- Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mahshid Hesami
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | | | - Maryam Hosseini Moghadam
- Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Amir Farjam Fazelifar
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Majid Maleki
- Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Samira Kalayinia
- Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.
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13
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Hong MH, Jang YJ, Yoon JJ, Lee HS, Kim HY, Kang DG. Dohongsamul-tang inhibits cardiac remodeling and fibrosis through calcineurin/NFAT and TGF-β/Smad2 signaling in cardiac hypertrophy. JOURNAL OF ETHNOPHARMACOLOGY 2024; 318:116844. [PMID: 37453625 DOI: 10.1016/j.jep.2023.116844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 06/19/2023] [Accepted: 06/22/2023] [Indexed: 07/18/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Dohongsammul-tang (DH) is a Korean traditional herbal medicine used to alleviate symptoms caused by extravasated blood. It is known to protect against cardiovascular diseases and promote blood circulation by activating blood circulation to dispel blood stasis. The DH based on the characteristics of its medicinal properties has discovered the potential of alleviating cardiac hypertrophy. Therefore, this study was performed to verify the pharmacological effect of DH on improving cardiovascular disorders and to demonstrate its mutual improvement effect on renal function. Furthermore, aim of this study is founding the new potential beyond the traditional medicinal efficacy of DH, a traditional medicine. AIM OF THE STUDY In cardiovascular disease, cardiac hypertrophy refers to a change in the shape of the heart's structure due to pressure overload. It is known that an increase in myofibrils causes thickening of the heart, resulting in high blood pressure. Therefore, suppressing cardiac hypertrophy may be a major factor in lowering the morbidity, mortality, and heart failure associated with cardiovascular disease. Therefore, the study was performed to investigate whether DH, traditionally used, has effects on improving and alleviating cardiac injury and fibrosis caused by cardiac hypertrophy. MATERIALS AND METHODS Dohongsamul-tang was composed of 6 herbal medicine and each material were boiled with 4 L distilled water for 2 h. The mixture for dohongsamul-tang centrifuged at 3000 rpm for 10 min and concentrated. The concentrated dohongsamul-tang extraction freeze-dried and sotred at 70 °C. The powder of dohongsamul-tang was diluted with distilled water and administered orally. In this study, pressure overload was induced by tying the transverse aortic arch, which is connected to the left ventricle, to the thickness of a 27G needle by performing a surgical operation. The resulting cardiac hypertrophy and heart remodeling was induced and maintained for 8 weeks. RESULTS The study administered propranolol and dohongsamul-tang orally for 10 weeks to investigate their effects on cardiac hypertrophy induced by transverse aortic contraction (TAC) surgery. Results showed that TAC group increased the left ventricle weight and decreased cardiac function, but dohongsamul-tang treatment attenuated these effects. The pressure-volume curve experiment revealed that dohongsamul-tang improved cardiovascular function, which was worsened by TAC group. Dohongsamul-tang treatment also downregulated collagen I and III through the TGF-β/Smad2 signaling pathway and improved hematological biomarkers of cardiac hypertrophy. In addition, dohongsamul-tang treatment improved renal function-related biomarkers, such as blood creatinine, blood urea nitrogen, and neutrophil gelatinase-associated lipocalin, which were increased by TAC-induced cardiac hypertrophy. CONCLUSIONS Taken together, dohongsamul-tang treatment inhibited cardiac remodeling due to pressure overload in the TAC-induced cardiac hypertrophy model, and this effect is thought to be manifested by improving the functional and morphological changes through the calcineurin/NFATc4 and reducing the cardiac fibrosis by suppressing TGF-β/Smad2 signaling pathways.
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Affiliation(s)
- Mi Hyeon Hong
- Hanbang Cardio-renal Research Center & Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan 54538, South Korea; College of Oriental Medicine and Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan 54538, South Korea.
| | - Youn Jae Jang
- Hanbang Cardio-renal Research Center & Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan 54538, South Korea; College of Oriental Medicine and Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan 54538, South Korea.
| | - Jung Joo Yoon
- Hanbang Cardio-renal Research Center & Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan 54538, South Korea.
| | - Ho Sub Lee
- Hanbang Cardio-renal Research Center & Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan 54538, South Korea; College of Oriental Medicine and Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan 54538, South Korea.
| | - Hye Yoom Kim
- Hanbang Cardio-renal Research Center & Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan 54538, South Korea.
| | - Dae Gill Kang
- Hanbang Cardio-renal Research Center & Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan 54538, South Korea; College of Oriental Medicine and Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan 54538, South Korea.
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14
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Son CO, Hong MH, Kim HY, Han BH, Seo CS, Lee HS, Yoon JJ, Kang DG. Sibjotang Protects against Cardiac Hypertrophy In Vitro and In Vivo. Life (Basel) 2023; 13:2307. [PMID: 38137908 PMCID: PMC10744393 DOI: 10.3390/life13122307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 10/19/2023] [Accepted: 10/26/2023] [Indexed: 12/24/2023] Open
Abstract
Cardiac hypertrophy is developed by various diseases such as myocardial infarction, valve diseases, hypertension, and aortic stenosis. Sibjotang (, Shizaotang, SJT), a classic formula in Korean traditional medicine, has been shown to modulate the equilibrium of body fluids and blood pressure. This research study sought to explore the impact and underlying process of Sibjotang on cardiotoxicity induced by DOX in H9c2 cells. In vitro, H9c2 cells were induced by DOX (1 μM) in the presence or absence of SJT (1-5 μg/mL) and incubated for 24 h. In vivo, SJT was administrated to isoproterenol (ISO)-induced cardiac hypertrophy mice (n = 8) at 100 mg/kg/day concentrations. Immunofluorescence staining revealed that SJT mitigated the enlargement of H9c2 cells caused by DOX in a dose-dependent way. Using SJT as a pretreatment notably suppressed the rise in cardiac hypertrophic marker levels induced by DOX. SJT inhibited the DOX-induced ERK1/2 and p38 MAPK signaling pathways. In addition, SJT significantly decreased the expression of the hypertrophy-associated transcription factor GATA binding factor 4 (GATA 4) induced by DOX. SJT also decreased hypertrophy-associated calcineurin and NFAT protein levels. Pretreatment with SJT significantly attenuated DOX-induced apoptosis-associated proteins such as Bax, caspase-3, and caspase-9 without affecting cell viability. In addition, the results of the in vivo study indicated that SJT significantly reduced the left ventricle/body weight ratio level. Administration of SJT reduced the expression of hypertrophy markers, such as ANP and BNP. These results suggest that SJT attenuates cardiac hypertrophy and heart failure induced by DOX or ISO through the inhibition of the calcineurin/NFAT/GATA4 pathway. Therefore, SJT may be a potential treatment for the prevention and treatment of cardiac hypertrophy that leads to heart failure.
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Affiliation(s)
- Chan-Ok Son
- Department of Ophthalmology, Konkuk University School of Medicine, Gwangjin-gu, Seoul 05030, Republic of Korea;
| | - Mi-Hyeon Hong
- Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, 460, Iksan-daero, Iksan, Jeonbuk 54538, Republic of Korea; (M.-H.H.); (H.-Y.K.); (B.-H.H.); (H.-S.L.)
| | - Hye-Yoom Kim
- Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, 460, Iksan-daero, Iksan, Jeonbuk 54538, Republic of Korea; (M.-H.H.); (H.-Y.K.); (B.-H.H.); (H.-S.L.)
| | - Byung-Hyuk Han
- Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, 460, Iksan-daero, Iksan, Jeonbuk 54538, Republic of Korea; (M.-H.H.); (H.-Y.K.); (B.-H.H.); (H.-S.L.)
| | - Chang-Seob Seo
- KM Science Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Republic of Korea;
| | - Ho-Sub Lee
- Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, 460, Iksan-daero, Iksan, Jeonbuk 54538, Republic of Korea; (M.-H.H.); (H.-Y.K.); (B.-H.H.); (H.-S.L.)
| | - Jung-Joo Yoon
- Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, 460, Iksan-daero, Iksan, Jeonbuk 54538, Republic of Korea; (M.-H.H.); (H.-Y.K.); (B.-H.H.); (H.-S.L.)
| | - Dae-Gill Kang
- Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, 460, Iksan-daero, Iksan, Jeonbuk 54538, Republic of Korea; (M.-H.H.); (H.-Y.K.); (B.-H.H.); (H.-S.L.)
- College of Oriental Medicine, Wonkwang University, 460, Iksan-daero, Iksan, Jeonbuk 54538, Republic of Korea
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15
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Zhang HN, Zhang M, Tian W, Quan W, Song F, Liu SY, Liu XX, Mo D, Sun Y, Gao YY, Ye W, Feng YD, Xing CY, Ye C, Zhou L, Meng JR, Cao W, Li XQ. Canonical transient receptor potential channel 1 aggravates myocardial ischemia-and-reperfusion injury by upregulating reactive oxygen species. J Pharm Anal 2023; 13:1309-1325. [PMID: 38174113 PMCID: PMC10759261 DOI: 10.1016/j.jpha.2023.08.018] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 08/28/2023] [Accepted: 08/29/2023] [Indexed: 01/05/2024] Open
Abstract
The canonical transient receptor potential channel (TRPC) proteins form Ca2+-permeable cation channels that are involved in various heart diseases. However, the roles of specific TRPC proteins in myocardial ischemia/reperfusion (I/R) injury remain poorly understood. We observed that TRPC1 and TRPC6 were highly expressed in the area at risk (AAR) in a coronary artery ligation induced I/R model. Trpc1-/- mice exhibited improved cardiac function, lower serum Troponin T and serum creatine kinase level, smaller infarct volume, less fibrotic scars, and fewer apoptotic cells after myocardial-I/R than wild-type or Trpc6-/- mice. Cardiomyocyte-specific knockdown of Trpc1 using adeno-associated virus 9 mitigated myocardial I/R injury. Furthermore, Trpc1 deficiency protected adult mouse ventricular myocytes (AMVMs) and HL-1 cells from death during hypoxia/reoxygenation (H/R) injury. RNA-sequencing-based transcriptome analysis revealed differential expression of genes related to reactive oxygen species (ROS) generation in Trpc1-/- cardiomyocytes. Among these genes, oxoglutarate dehydrogenase-like (Ogdhl) was markedly downregulated. Moreover, Trpc1 deficiency impaired the calcineurin (CaN)/nuclear factor-kappa B (NF-κB) signaling pathway in AMVMs. Suppression of this pathway inhibited Ogdhl upregulation and ROS generation in HL-1 cells under H/R conditions. Chromatin immunoprecipitation assays confirmed NF-κB binding to the Ogdhl promoter. The cardioprotective effect of Trpc1 deficiency was canceled out by overexpression of NF-κB and Ogdhl in cardiomyocytes. In conclusion, our findings reveal that TRPC1 is upregulated in the AAR following myocardial I/R, leading to increased Ca2+ influx into associated cardiomyocytes. Subsequently, this upregulates Ogdhl expression through the CaN/NF-κB signaling pathway, ultimately exacerbating ROS production and aggravating myocardial I/R injury.
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Affiliation(s)
- Hui-Nan Zhang
- Department of Health Management, Second Affiliated Hospital, Fourth Military Medical University, Xi'an, 710038, China
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Meng Zhang
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
- Shaanxi Key Laboratory of “Qin Medicine” Research and Development, Shaanxi Administration of Traditional Chinese Medicine, Xi'an, 710032, China
| | - Wen Tian
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
- Shaanxi Key Laboratory of “Qin Medicine” Research and Development, Shaanxi Administration of Traditional Chinese Medicine, Xi'an, 710032, China
| | - Wei Quan
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
- Shaanxi Key Laboratory of “Qin Medicine” Research and Development, Shaanxi Administration of Traditional Chinese Medicine, Xi'an, 710032, China
| | - Fan Song
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
- Institute of Materia Medica, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Shao-Yuan Liu
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
- Shaanxi Key Laboratory of “Qin Medicine” Research and Development, Shaanxi Administration of Traditional Chinese Medicine, Xi'an, 710032, China
| | - Xiao-Xiao Liu
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Dan Mo
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Yang Sun
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Yuan-Yuan Gao
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Wen Ye
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
- Shaanxi Key Laboratory of “Qin Medicine” Research and Development, Shaanxi Administration of Traditional Chinese Medicine, Xi'an, 710032, China
| | - Ying-Da Feng
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
- Shaanxi Key Laboratory of “Qin Medicine” Research and Development, Shaanxi Administration of Traditional Chinese Medicine, Xi'an, 710032, China
| | - Chang-Yang Xing
- Department of Ultrasound Diagnostics, Second Affiliated Hospital, Fourth Military Medical University, Xi'an, 710038, China
| | - Chen Ye
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Lei Zhou
- Department of Pharmacy, School of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Jing-Ru Meng
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
- Shaanxi Key Laboratory of “Qin Medicine” Research and Development, Shaanxi Administration of Traditional Chinese Medicine, Xi'an, 710032, China
| | - Wei Cao
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
- Department of Pharmacy, School of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Xiao-Qiang Li
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
- Shaanxi Key Laboratory of “Qin Medicine” Research and Development, Shaanxi Administration of Traditional Chinese Medicine, Xi'an, 710032, China
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16
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Dondi C, Vogler G, Gupta A, Walls SM, Kervadec A, Romero MR, Diop SB, Goode J, Thomas JB, Colas AR, Bodmer R, Montminy M, Ocorr K. The nutrient sensor CRTC & Sarcalumenin / Thinman represent a new pathway in cardiac hypertrophy. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.02.560407. [PMID: 37873259 PMCID: PMC10592890 DOI: 10.1101/2023.10.02.560407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2023]
Abstract
Obesity and type 2 diabetes are at epidemic levels and a significant proportion of these patients are diagnosed with left ventricular hypertrophy. CREB R egulated T ranscription C o-activator ( CRTC ) is a key regulator of metabolism in mammalian hepatocytes, where it is activated by calcineurin (CaN) to increase expression of gluconeogenic genes. CaN is known its role in pathological cardiac hypertrophy, however, a role for CRTC in the heart has not been identified. In Drosophila , CRTC null mutants have little body fat and exhibit severe cardiac restriction, myofibrillar disorganization, cardiac fibrosis and tachycardia, all hallmarks of heart disease. Cardiac-specific knockdown of CRTC , or its coactivator CREBb , mimicked the reduced body fat and heart defects of CRTC null mutants. Comparative gene expression in CRTC loss- or gain-of-function fly hearts revealed contra-regulation of genes involved in glucose, fatty acid, and amino acid metabolism, suggesting that CRTC also acts as a metabolic switch in the heart. Among the contra-regulated genes with conserved CREB binding sites, we identified the fly ortholog of Sarcalumenin, which is a Ca 2+ -binding protein in the sarcoplasmic reticulum. Cardiac knockdown recapitulated the loss of CRTC cardiac restriction and fibrotic phenotypes, suggesting it is a downstream effector of CRTC we named thinman ( tmn ). Importantly, cardiac overexpression of either CaN or CRTC in flies caused hypertrophy that was reversed in a CRTC mutant background, suggesting CRTC mediates hypertrophy downstream of CaN, perhaps as an alternative to NFAT. CRTC novel role in the heart is likely conserved in vertebrates as knockdown in zebrafish also caused cardiac restriction, as in fl ies. These data suggest that CRTC is involved in myocardial cell maintenance and that CaN-CRTC- Sarcalumenin/ tmn signaling represents a novel and conserved pathway underlying cardiac hypertrophy.
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17
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Li X, Zhang Y, Jin Q, Song Q, Fan C, Jiao Y, Yang C, Chang J, Dong Z, Que Y. Silicate Ions Derived from Calcium Silicate Extract Decelerate Ang II-Induced Cardiac Remodeling. Tissue Eng Regen Med 2023; 20:671-681. [PMID: 36920676 PMCID: PMC10352221 DOI: 10.1007/s13770-023-00523-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 01/16/2023] [Accepted: 01/18/2023] [Indexed: 03/16/2023] Open
Abstract
BACKGROUND Pathological cardiac hypertrophy is one of the main activators of heart failure. Currently, no drug can completely reverse or inhibit the development of pathological cardiac hypertrophy. To this end, we proposed a silicate ion therapy based on extract derived from calcium silicate (CS) bioceramics for the treatment of angiotensin II (Ang II) induced cardiac hypertrophy. METHODS In this study, the Ang II induced cardiac hypertrophy mouse model was established, and the silicate ion extract was injected to mice intravenously. The cardiac function was evaluated by using a high-resolution Vevo 3100 small animal ultrasound imaging system. Wheat germ Agglutinin, Fluo4-AM staining and immunofluorescent staining was conducted to assess the cardiac hypertrophy, intracellular calcium and angiogenesis of heart tissue, respectively. RESULTS The in vitro results showed that silicate ions could inhibit the cell size of cardiomyocytes, reduce cardiac hypertrophic gene expression, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and β-myosin heavy chain (β-MHC), decrease the content of intracellular calcium induced by Ang II. In vivo experiments in mice confirmed that intravenous injection of silicate ions could remarkably inhibit the cardiac hypertrophy and promote the formation of capillaries, further alleviating Ang II-induced cardiac function disorder. CONCLUSION This study demonstrated that the released silicate ions from CS possessed potential value as a novel therapeutic strategy of pathological cardiac hypertrophy, which provided a new insight for clinical trials.
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Affiliation(s)
- Xin Li
- School of Mechanical Engineering, Chengdu University, Chengdu, 610106, China
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, China
| | - Yanxin Zhang
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, China
| | - Qishu Jin
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, China
| | - Qiaoyu Song
- School of Mechanical Engineering, Chengdu University, Chengdu, 610106, China
| | - Chen Fan
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, China
| | - Yiren Jiao
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, China
| | - Chen Yang
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, China
| | - Jiang Chang
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, China
- Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Dingxi Road, Shanghai, 200050, China
| | - Zhihong Dong
- School of Mechanical Engineering, Chengdu University, Chengdu, 610106, China.
| | - Yumei Que
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, China.
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18
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Petersen M, Schmiedel N, Dierck F, Hille S, Remes A, Senger F, Schmidt I, Lüllmann-Rauch R, Müller OJ, Frank D, Rangrez AY, Frey N, Kuhn C. Fibin regulates cardiomyocyte hypertrophy and causes protein-aggregate-associated cardiomyopathy in vivo. Front Mol Biosci 2023; 10:1169658. [PMID: 37342207 PMCID: PMC10278231 DOI: 10.3389/fmolb.2023.1169658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 05/16/2023] [Indexed: 06/22/2023] Open
Abstract
Despite the identification of numerous molecular pathways modulating cardiac hypertrophy its pathogenesis is not completely understood. In this study we define an unexpected role for Fibin ("fin bud initiation factor homolog") in cardiomyocyte hypertrophy. Via gene expression profiling in hypertrophic murine hearts after transverse aortic constriction we found a significant induction of Fibin. Moreover, Fibin was upregulated in another mouse model of cardiac hypertrophy (calcineurin-transgenics) as well as in patients with dilated cardiomyopathy. Immunoflourescence microscopy revealed subcellular localization of Fibin at the sarcomeric z-disc. Overexpression of Fibin in neonatal rat ventricular cardiomyocytes revealed a strong anti-hypertrophic effect through inhibiting both, NFAT- and SRF-dependent signalling. In contrast, transgenic mice with cardiac-restricted overexpression of Fibin developed dilated cardiomyopathy, accompanied by induction of hypertrophy-associated genes. Moreover, Fibin overexpression accelerated the progression to heart failure in the presence of prohypertrophic stimuli such as pressure overload and calcineurin overexpression. Histological and ultrastructural analyses surprisingly showed large protein aggregates containing Fibin. On the molecular level, aggregate formation was accompanied by an induction of the unfolded protein response subsequent UPR-mediated apoptosis and autophagy. Taken together, we identified Fibin as a novel potent negative regulator of cardiomyocyte hypertrophy in vitro. Yet, heart-specific Fibin overexpression in vivo causes development of a protein-aggregate-associated cardiomyopathy. Because of close similarities to myofibrillar myopathies, Fibin represents a candidate gene for cardiomyopathy and Fibin transgenic mice may provide additional mechanistic insight into aggregate formation in these diseases.
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Affiliation(s)
- Matthias Petersen
- Department of Internal Medicine III, University Medical Center of Schleswig-Holstein, Campus Kiel, Kiel, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Kiel, Germany
| | - Nesrin Schmiedel
- Department of Internal Medicine III, University Medical Center of Schleswig-Holstein, Campus Kiel, Kiel, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Kiel, Germany
| | - Franziska Dierck
- Department of Internal Medicine III, University Medical Center of Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Susanne Hille
- Department of Internal Medicine III, University Medical Center of Schleswig-Holstein, Campus Kiel, Kiel, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Kiel, Germany
| | - Anca Remes
- Department of Internal Medicine III, University Medical Center of Schleswig-Holstein, Campus Kiel, Kiel, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Kiel, Germany
| | - Frauke Senger
- Department of Internal Medicine III, University Medical Center of Schleswig-Holstein, Campus Kiel, Kiel, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Kiel, Germany
| | - Inga Schmidt
- Department of Internal Medicine III, University Medical Center of Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | | | - Oliver J. Müller
- Department of Internal Medicine III, University Medical Center of Schleswig-Holstein, Campus Kiel, Kiel, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Kiel, Germany
| | - Derk Frank
- Department of Internal Medicine III, University Medical Center of Schleswig-Holstein, Campus Kiel, Kiel, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Kiel, Germany
| | - Ashraf Y. Rangrez
- Department of Cardiology, Angiology and Pneumology, Heidelberg University Hospital, Heidelberg, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany
| | - Norbert Frey
- Department of Cardiology, Angiology and Pneumology, Heidelberg University Hospital, Heidelberg, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany
| | - Christian Kuhn
- Department of Internal Medicine III, University Medical Center of Schleswig-Holstein, Campus Kiel, Kiel, Germany
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19
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Matsuno M, Yokoe S, Nagatsuka T, Morihara H, Moriwaki K, Asahi M. O-GlcNAcylation-induced GSK-3β activation deteriorates pressure overload-induced heart failure via lack of compensatory cardiac hypertrophy in mice. Front Endocrinol (Lausanne) 2023; 14:1122125. [PMID: 37033243 PMCID: PMC10073727 DOI: 10.3389/fendo.2023.1122125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 02/27/2023] [Indexed: 04/11/2023] Open
Abstract
O-GlcNAc transferase (OGT) modulates many functions of proteins via O-GlcNAcylation that adds O-linked β-N-acetylglucosamine (O-GlcNAc) to the serine/threonine residues of proteins. However, the role of O-GlcNAcylation in cardiac remodeling and function is not fully understood. To examine the effect of O-GlcNAcylation on pressure overload-induced cardiac hypertrophy and subsequent heart failure, transverse aortic constriction (TAC) surgery was performed in wild type (WT) and Ogt transgenic (Ogt-Tg) mice. Four weeks after TAC (TAC4W), the heart function of Ogt-Tg mice was significantly lower than that of WT mice (reduced fractional shortening and increased ANP levels). The myocardium of left ventricle (LV) in Ogt-Tg mice became much thinner than that in WT mice. Moreover, compared to the heart tissues of WT mice, O-GlcNAcylation of GSK-3β at Ser9 was increased and phosphorylation of GSK-3β at Ser9 was reduced in the heart tissues of Ogt-Tg mice, resulting in its activation and subsequent inactivation of nuclear factor of activated T cell (NFAT) activity. Finally, the thinned LV wall and reduced cardiac function induced by TAC4W in Ogt-Tg mice was reversed by the treatment of a GSK-3β inhibitor, TDZD-8. These results imply that augmented O-GlcNAcylation exacerbates pressure overload-induced heart failure due to a lack of compensatory cardiac hypertrophy via O-GlcNAcylation of GSK-3β, which deprives the phosphorylation site of GSK-3β to constantly inactivate NFAT activity to prevent cardiac hypertrophy. Our findings may provide a new therapeutic strategy for cardiac hypertrophy and subsequent heart failure.
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Affiliation(s)
- Mahito Matsuno
- Department of Pharmacology, Faculty of Medicine, Osaka Medical and Pharmaceutical University, Osaka, Japan
| | - Shunichi Yokoe
- Department of Pharmacology, Faculty of Medicine, Osaka Medical and Pharmaceutical University, Osaka, Japan
| | - Takehiro Nagatsuka
- Center for Medical Research & Development, Osaka Medical and Pharmaceutical University, Osaka, Japan
| | - Hirofumi Morihara
- Department of Pharmacology, Faculty of Medicine, Osaka Medical and Pharmaceutical University, Osaka, Japan
| | - Kazumasa Moriwaki
- Department of Pharmacology, Faculty of Medicine, Osaka Medical and Pharmaceutical University, Osaka, Japan
| | - Michio Asahi
- Department of Pharmacology, Faculty of Medicine, Osaka Medical and Pharmaceutical University, Osaka, Japan
- *Correspondence: Michio Asahi,
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20
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Muacevic A, Adler JR, Doutsini S, Adamidou F, Zafeiropoulos S, Koliastasis L, Manani C, Pliakos I, Papavramidis T. Effect of Parathyroidectomy on Left Ventricular Mass Index in Patients With Primary Hyperparathyroidism. Cureus 2023; 15:e33429. [PMID: 36751183 PMCID: PMC9899328 DOI: 10.7759/cureus.33429] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/04/2023] [Indexed: 01/09/2023] Open
Abstract
Aim Primary hyperthyroidism (PHPT) is known to affect left ventricular structure and function and may contribute to increased cardiovascular morbidity and mortality. Whether parathyroidectomy (PTX) reverses left ventricular hypertrophy/remodeling among PHPT patients remains controversial. Method In this prospective, single-center study, we enrolled patients with the diagnosis of PHPT who were scheduled for PTX. Patients underwent a complete biochemical workup and an echocardiographic examination at baseline and a six-month follow-up. The primary objective was to compare the left ventricular mass index (LVMI) at baseline and six-month follow-up. Result Eighteen patients (15 female, three male, mean age 58.7 years) were enrolled. PTH and serum calcium returned to normal immediately post-PTX and remained normal at six months. LVMI at baseline was within normal limits and reduced further at the six-month follow-up. The left ventricular ejection fraction was in the normal range before the PTX and remained unchanged during follow-up. Conclusion Curative PTX reduced LVMI further within the normal range at six months in patients with asymptomatic hyperparathyroidism, providing evidence for benefit in an important non-traditional disease manifestation.
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21
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Tarasov KV, Chakir K, Riordon DR, Lyashkov AE, Ahmet I, Perino MG, Silvester AJ, Zhang J, Wang M, Lukyanenko YO, Qu JH, Barrera MCR, Juhaszova M, Tarasova YS, Ziman B, Telljohann R, Kumar V, Ranek M, Lammons J, Bychkov R, de Cabo R, Jun S, Keceli G, Gupta A, Yang D, Aon MA, Adamo L, Morrell CH, Otu W, Carroll C, Chambers S, Paolocci N, Huynh T, Pacak K, Weiss R, Field L, Sollott SJ, Lakatta EG. A remarkable adaptive paradigm of heart performance and protection emerges in response to marked cardiac-specific overexpression of ADCY8. eLife 2022; 11:e80949. [PMID: 36515265 PMCID: PMC9822292 DOI: 10.7554/elife.80949] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 12/08/2022] [Indexed: 12/15/2022] Open
Abstract
Adult (3 month) mice with cardiac-specific overexpression of adenylyl cyclase (AC) type VIII (TGAC8) adapt to an increased cAMP-induced cardiac workload (~30% increases in heart rate, ejection fraction and cardiac output) for up to a year without signs of heart failure or excessive mortality. Here, we show classical cardiac hypertrophy markers were absent in TGAC8, and that total left ventricular (LV) mass was not increased: a reduced LV cavity volume in TGAC8 was encased by thicker LV walls harboring an increased number of small cardiac myocytes, and a network of small interstitial proliferative non-cardiac myocytes compared to wild type (WT) littermates; Protein synthesis, proteosome activity, and autophagy were enhanced in TGAC8 vs WT, and Nrf-2, Hsp90α, and ACC2 protein levels were increased. Despite increased energy demands in vivo LV ATP and phosphocreatine levels in TGAC8 did not differ from WT. Unbiased omics analyses identified more than 2,000 transcripts and proteins, comprising a broad array of biological processes across multiple cellular compartments, which differed by genotype; compared to WT, in TGAC8 there was a shift from fatty acid oxidation to aerobic glycolysis in the context of increased utilization of the pentose phosphate shunt and nucleotide synthesis. Thus, marked overexpression of AC8 engages complex, coordinate adaptation "circuity" that has evolved in mammalian cells to defend against stress that threatens health or life (elements of which have already been shown to be central to cardiac ischemic pre-conditioning and exercise endurance cardiac conditioning) that may be of biological significance to allow for proper healing in disease states such as infarction or failure of the heart.
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Affiliation(s)
- Kirill V Tarasov
- Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Khalid Chakir
- Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Daniel R Riordon
- Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Alexey E Lyashkov
- Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Ismayil Ahmet
- Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Maria Grazia Perino
- Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Allwin Jennifa Silvester
- Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Jing Zhang
- Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Mingyi Wang
- Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Yevgeniya O Lukyanenko
- Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Jia-Hua Qu
- Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Miguel Calvo-Rubio Barrera
- Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Magdalena Juhaszova
- Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Yelena S Tarasova
- Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Bruce Ziman
- Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Richard Telljohann
- Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Vikas Kumar
- Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Mark Ranek
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - John Lammons
- Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Rostislav Bychkov
- Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Rafael de Cabo
- Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Seungho Jun
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Gizem Keceli
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Ashish Gupta
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Dongmei Yang
- Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Miguel A Aon
- Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Luigi Adamo
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Christopher H Morrell
- Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Walter Otu
- Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Cameron Carroll
- Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Shane Chambers
- Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Nazareno Paolocci
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Thanh Huynh
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of HealthBethesdaUnited States
| | - Karel Pacak
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of HealthBethesdaUnited States
| | - Robert Weiss
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Loren Field
- Kraennert Institute of Cardiology, Indiana University School of MedicineIdianapolisUnited States
| | - Steven J Sollott
- Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Edward G Lakatta
- Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
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22
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Hamilton S, Terentyev D. ER stress and calcium-dependent arrhythmias. Front Physiol 2022; 13:1041940. [PMID: 36425292 PMCID: PMC9679650 DOI: 10.3389/fphys.2022.1041940] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Accepted: 10/24/2022] [Indexed: 11/11/2022] Open
Abstract
The sarcoplasmic reticulum (SR) plays the key role in cardiac function as the major source of Ca2+ that activates cardiomyocyte contractile machinery. Disturbances in finely-tuned SR Ca2+ release by SR Ca2+ channel ryanodine receptor (RyR2) and SR Ca2+ reuptake by SR Ca2+-ATPase (SERCa2a) not only impair contraction, but also contribute to cardiac arrhythmia trigger and reentry. Besides being the main Ca2+ storage organelle, SR in cardiomyocytes performs all the functions of endoplasmic reticulum (ER) in other cell types including protein synthesis, folding and degradation. In recent years ER stress has become recognized as an important contributing factor in many cardiac pathologies, including deadly ventricular arrhythmias. This brief review will therefore focus on ER stress mechanisms in the heart and how these changes can lead to pro-arrhythmic defects in SR Ca2+ handling machinery.
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Affiliation(s)
- Shanna Hamilton
- Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, United States,Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States,*Correspondence: Shanna Hamilton,
| | - Dmitry Terentyev
- Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, United States,Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States
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23
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Wei Y, Cai J, Zhu R, Xu K, Li H, Li J. Function and therapeutic potential of transient receptor potential ankyrin 1 in fibrosis. Front Pharmacol 2022; 13:1014041. [PMID: 36278189 PMCID: PMC9582847 DOI: 10.3389/fphar.2022.1014041] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 09/26/2022] [Indexed: 11/18/2022] Open
Abstract
The transient receptor potential (TRP) protein superfamily is a special group of cation channels expressed in different cell types and signaling pathways. In this review, we focus on TRPA1 (transient receptor potential ankyrin 1), an ion channel in this family that exists in the cell membrane and shows a different function from other TRP channels. TRPA1 usually has a special activation effect that can induce cation ions, especially calcium ions, to flow into activated cells. In this paper, we review the role of TRPA1 in fibroblasts. To clarify the relationship between fibroblasts and TRPA1, we have also paid special attention to the interactions between TRPA1 and inflammatory factors leading to fibroblast activation. TRPA1 has different functions in the fibrosis process in different organs, and there have also been interesting discussions of the mechanism of TRPA1 in fibroblasts. Therefore, this review aims to describe the function of TRP channels in controlling fibrosis through fibroblasts in different organ inflammatory and immune-mediated diseases. We attempt to prove that TRPA1 is a target for fibrosis. In fact, some clinical trials have already proven that TRPA1 is a potential adjuvant therapy for treating fibrosis.
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Affiliation(s)
- Yicheng Wei
- Third Affiliated Hospital of Shanghai University/Wenzhou People’s Hospital, Wenzhou, China
- Shanghai Putuo Central School of Clinical Medicine, Anhui Medical University, Hefei, Anhui, China
- Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jialuo Cai
- Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Ruiqiu Zhu
- Shanghai Putuo Central School of Clinical Medicine, Anhui Medical University, Hefei, Anhui, China
- Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ke Xu
- Musculoskeletal Organoid Research Center, Institute of Translational Medicine, Shanghai University, Shanghai, China
- Wenzhou Institute of Shanghai University, Wenzhou, China
- *Correspondence: Ke Xu, , ; Hongchang Li, ; Jianxin Li,
| | - Hongchang Li
- Department of General Surgery, Institute of Fudan–Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, China
- *Correspondence: Ke Xu, , ; Hongchang Li, ; Jianxin Li,
| | - Jianxin Li
- Third Affiliated Hospital of Shanghai University/Wenzhou People’s Hospital, Wenzhou, China
- *Correspondence: Ke Xu, , ; Hongchang Li, ; Jianxin Li,
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Can Blebbistatin block the hypertrophy status in the zebrafish exvivo cardiac model? Biochim Biophys Acta Mol Basis Dis 2022; 1868:166471. [PMID: 35750268 DOI: 10.1016/j.bbadis.2022.166471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 05/31/2022] [Accepted: 06/16/2022] [Indexed: 11/23/2022]
Abstract
Ex-vivo simple models are powered tools to study cardiac hypertrophy. It is possible to control the activation of critical genes and thus test the effects of drug therapies before the in vivo tests. A zebrafish cardiac hypertrophy developed by 500 μM phenylephrine (PE) treatment in ex vivo culture has been demonstrated to activate the essential expression of the embryonal genes. These genes are the same as those described in several previous pieces of research on hypertrophic pathology in humans. The efficacy of the chemical drug Blebbistatin (BL) on hypertrophy induced ex vivo cultured hearts is studied in this research. BL can inhibit the myosins and the calcium wave in counteracting the hypertrophy status caused by PE. Samples treated with PE, BL and PE simultaneously, or pre/post-treatment with BL, have been analysed for the embryonal gene activation concerning the hypertrophy status. The qRTPCR has shown an inhibitory effect of BL treatments on the microRNAs downregulation with the consequent low expression of essential embryonal genes. In particular, BL seems to be effective in blocking the hyperplasia of the epicardium but less effective in myocardium hypertrophy. The model can make it possible to obtain knowledge on the transduction pathways activated by BL and investigate the potential use of this drug in treating cardiac hypertrophy in humans.
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25
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Patel N, Yaqoob MM, Aksentijevic D. Cardiac metabolic remodelling in chronic kidney disease. Nat Rev Nephrol 2022; 18:524-537. [DOI: 10.1038/s41581-022-00576-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/14/2022] [Indexed: 11/09/2022]
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Tamayo M, Martín-Nunes L, Piedras MJ, Martin-Calvo M, Martí-Morente D, Gil-Fernández M, Gómez-Hurtado N, Moro MÁ, Bosca L, Fernández-Velasco M, Delgado C. The Aryl Hydrocarbon Receptor Ligand FICZ Improves Left Ventricular Remodeling and Cardiac Function at the Onset of Pressure Overload-Induced Heart Failure in Mice. Int J Mol Sci 2022; 23:5403. [PMID: 35628213 PMCID: PMC9141655 DOI: 10.3390/ijms23105403] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 05/06/2022] [Accepted: 05/10/2022] [Indexed: 02/07/2023] Open
Abstract
Adverse ventricular remodeling is the heart's response to damaging stimuli and is linked to heart failure and poor prognosis. Formyl-indolo [3,2-b] carbazole (FICZ) is an endogenous ligand for the aryl hydrocarbon receptor (AhR), through which it exerts pleiotropic effects including protection against inflammation, fibrosis, and oxidative stress. We evaluated the effect of AhR activation by FICZ on the adverse ventricular remodeling that occurs in the early phase of pressure overload in the murine heart induced by transverse aortic constriction (TAC). Cardiac structure and function were evaluated by cardiac magnetic resonance imaging (CMRI) before and 3 days after Sham or TAC surgery in mice treated with FICZ or with vehicle, and cardiac tissue was used for biochemical studies. CMRI analysis revealed that FICZ improved cardiac function and attenuated cardiac hypertrophy. These beneficial effects involved the inhibition of the hypertrophic calcineurin/NFAT pathway, transcriptional reduction in pro-fibrotic genes, and antioxidant effects mediated by the NRF2/NQO1 pathway. Overall, our findings provide new insight into the role of cardiac AhR signaling in the injured heart.
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Affiliation(s)
- María Tamayo
- Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), CIBER de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain; (M.T.); (L.M.-N.); (M.J.P.); (M.M.-C.); (D.M.-M.); (M.G.-F.); (N.G.-H.); (L.B.); (M.F.-V.)
| | - Laura Martín-Nunes
- Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), CIBER de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain; (M.T.); (L.M.-N.); (M.J.P.); (M.M.-C.); (D.M.-M.); (M.G.-F.); (N.G.-H.); (L.B.); (M.F.-V.)
| | - María José Piedras
- Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), CIBER de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain; (M.T.); (L.M.-N.); (M.J.P.); (M.M.-C.); (D.M.-M.); (M.G.-F.); (N.G.-H.); (L.B.); (M.F.-V.)
- Facultad de Medicina, Universidad Francisco de Vitoria (UFV), 28223 Madrid, Spain
| | - María Martin-Calvo
- Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), CIBER de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain; (M.T.); (L.M.-N.); (M.J.P.); (M.M.-C.); (D.M.-M.); (M.G.-F.); (N.G.-H.); (L.B.); (M.F.-V.)
| | - Daniel Martí-Morente
- Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), CIBER de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain; (M.T.); (L.M.-N.); (M.J.P.); (M.M.-C.); (D.M.-M.); (M.G.-F.); (N.G.-H.); (L.B.); (M.F.-V.)
| | - Marta Gil-Fernández
- Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), CIBER de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain; (M.T.); (L.M.-N.); (M.J.P.); (M.M.-C.); (D.M.-M.); (M.G.-F.); (N.G.-H.); (L.B.); (M.F.-V.)
- Innate Immune Response Group, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain
| | - Nieves Gómez-Hurtado
- Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), CIBER de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain; (M.T.); (L.M.-N.); (M.J.P.); (M.M.-C.); (D.M.-M.); (M.G.-F.); (N.G.-H.); (L.B.); (M.F.-V.)
| | - María Ángeles Moro
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, 28029 Madrid, Spain;
| | - Lisardo Bosca
- Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), CIBER de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain; (M.T.); (L.M.-N.); (M.J.P.); (M.M.-C.); (D.M.-M.); (M.G.-F.); (N.G.-H.); (L.B.); (M.F.-V.)
| | - María Fernández-Velasco
- Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), CIBER de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain; (M.T.); (L.M.-N.); (M.J.P.); (M.M.-C.); (D.M.-M.); (M.G.-F.); (N.G.-H.); (L.B.); (M.F.-V.)
- Innate Immune Response Group, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain
| | - Carmen Delgado
- Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), CIBER de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain; (M.T.); (L.M.-N.); (M.J.P.); (M.M.-C.); (D.M.-M.); (M.G.-F.); (N.G.-H.); (L.B.); (M.F.-V.)
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27
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Hoepfner J, Leonardy J, Lu D, Schmidt K, Hunkler HJ, Biß S, Foinquinos A, Xiao K, Regalla K, Ramanujam D, Engelhardt S, Bär C, Thum T. The long non-coding RNA NRON promotes the development of cardiac hypertrophy in the murine heart. Mol Ther 2022; 30:1265-1274. [PMID: 34856383 PMCID: PMC8899598 DOI: 10.1016/j.ymthe.2021.11.018] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 10/13/2021] [Accepted: 11/27/2021] [Indexed: 10/19/2022] Open
Abstract
Physiological and pathological cardiovascular processes are tightly regulated by several cellular mechanisms. Non-coding RNAs, including long non-coding RNAs (lncRNAs), represent one important class of molecules involved in regulatory processes within the cell. The lncRNA non-coding repressor of NFAT (NRON) was described as a repressor of the nuclear factor of activated T cells (NFAT) in different in vitro studies. Although the calcineurin/NFAT-signaling pathway is one of the most important pathways in pathological cardiac hypertrophy, a potential regulation of hypertrophy by NRON in vivo has remained unclear. Applying subcellular fractionation and RNA fluorescence in situ hybridization (RNA-FISH), we found that, unlike what is known from T cells, in cardiomyocytes, NRON predominantly localizes to the nucleus. Hypertrophic stimulation in neonatal mouse cardiomyocytes led to a downregulation of NRON, while NRON overexpression led to an increase in expression of hypertrophic markers. To functionally investigate NRON in vivo, we used a mouse model of transverse aortic constriction (TAC)-induced hypertrophy and performed NRON gain- and loss-of-function experiments. Cardiomyocyte-specific NRON overexpression in vivo exacerbated TAC-induced hypertrophy, whereas cardiomyocyte-specific NRON deletion attenuated cardiac hypertrophy in mice. Heart weight, cardiomyocyte cell size, hypertrophic marker gene expression, and left ventricular mass showed a NRON-dependent regulation upon TAC-induced hypertrophy. In line with this, transcriptome profiling revealed an enrichment of anti-hypertrophic signaling pathways upon NRON-knockout during TAC-induced hypertrophy. This set of data refutes the hypothesized anti-hypertrophic role of NRON derived from in vitro studies in non-cardiac cells and suggests a novel regulatory function of NRON in the heart in vivo.
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Affiliation(s)
- Jeannine Hoepfner
- Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Julia Leonardy
- Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Dongchao Lu
- Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Kevin Schmidt
- Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Hannah J. Hunkler
- Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Sinje Biß
- Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Ariana Foinquinos
- Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Ke Xiao
- Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Kumarswamy Regalla
- Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Deepak Ramanujam
- Institute of Pharmacology and Toxicology, Technical University Munich, 80802 Munich, Germany,DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, 80802 Munich, Germany
| | - Stefan Engelhardt
- Institute of Pharmacology and Toxicology, Technical University Munich, 80802 Munich, Germany,DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, 80802 Munich, Germany
| | - Christian Bär
- Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; REBIRTH Center for Translational Regenerative Medicine, Hannover Medical School, 30625 Hannover, Germany; Fraunhofer Institute for Toxicology and Experimental Medicine, 30625 Hannover, Germany.
| | - Thomas Thum
- Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; REBIRTH Center for Translational Regenerative Medicine, Hannover Medical School, 30625 Hannover, Germany; Fraunhofer Institute for Toxicology and Experimental Medicine, 30625 Hannover, Germany.
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28
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Ritchie JA, Ng JQ, Kemi OJ. When one says yes and the other says no; does calcineurin participate in physiologic cardiac hypertrophy? ADVANCES IN PHYSIOLOGY EDUCATION 2022; 46:84-95. [PMID: 34762541 DOI: 10.1152/advan.00104.2021] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 11/08/2021] [Indexed: 06/13/2023]
Abstract
Developing engaging activities that build skills for understanding and appreciating research is important for undergraduate and postgraduate science students. Comparing and contrasting opposing research studies does this, and more: it also appropriately for these cohorts challenges higher level cognitive processing. Here, we present and discuss one such scenario, that of calcineurin in the heart and its response to exercise training. This scenario is further accentuated by the existence of only two studies. The background is that regular aerobic endurance exercise training stimulates the heart to physiologically adapt to chronically increase its ability to produce a greater cardiac output to meet the increased demand for oxygenated blood in working muscles, and this happens by two main mechanisms: 1) increased cardiac contractile function and 2) physiologic hypertrophy. The major underlying mechanisms have been delineated over the last decades, but one aspect has not been resolved: the potential role of calcineurin in modulating physiologic hypertrophy. This is partly because the existing research has provided opposing and contrasting findings, one line showing that exercise training does activate cardiac calcineurin in conjunction with myocardial hypertrophy, but another line showing that exercise training does not activate cardiac calcineurin even if myocardial hypertrophy is blatantly occurring. Here, we review and present the current evidence in the field and discuss reasons for this controversy. We present real-life examples from physiology research and discuss how this may enhance student engagement and participation, widen the scope of learning, and thereby also further facilitate higher level cognitive processing.
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Affiliation(s)
- Jonathan A Ritchie
- School of Medicine, Dentistry and Nursing, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Jun Q Ng
- School of Life Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Ole J Kemi
- School of Life Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, United Kingdom
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29
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Winkle AJ, Nassal DM, Shaheen R, Thomas E, Mohta S, Gratz D, Weinberg SH, Hund TJ. Emerging therapeutic targets for cardiac hypertrophy. Expert Opin Ther Targets 2022; 26:29-40. [PMID: 35076342 PMCID: PMC8885901 DOI: 10.1080/14728222.2022.2031974] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 01/17/2022] [Indexed: 01/29/2023]
Abstract
INTRODUCTION Cardiac hypertrophy is associated with adverse outcomes across cardiovascular disease states. Despite strides over the last three decades in identifying molecular and cellular mechanisms driving hypertrophy, the link between pathophysiological stress stimuli and specific myocyte/heart growth profiles remains unclear. Moreover, the optimal strategy for preventing pathology in the setting of hypertrophy remains controversial. AREAS COVERED This review discusses molecular mechanisms underlying cardiac hypertrophy with a focus on factors driving the orientation of myocyte growth and the impact on heart function. We highlight recent work showing a novel role for the spectrin-based cytoskeleton, emphasizing regulation of myocyte dimensions but not hypertrophy per se. Finally, we consider opportunities for directing the orientation of myocyte growth in response to hypertrophic stimuli as an alternative therapeutic approach. Relevant publications on the topic were identified through Pubmed with open-ended search dates. EXPERT OPINION To define new therapeutic avenues, more precision is required when describing changes in myocyte and heart structure/function in response to hypertrophic stimuli. Recent developments in computational modeling of hypertrophic networks, in concert with more refined experimental approaches will catalyze translational discovery to advance the field and further our understanding of cardiac hypertrophy and its relationship with heart disease.
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Affiliation(s)
- Alex J. Winkle
- The Frick Center for Heart Failure and Arrhythmia, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA
- Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH, USA
| | - Drew M. Nassal
- The Frick Center for Heart Failure and Arrhythmia, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA
- Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH, USA
| | - Rebecca Shaheen
- The Frick Center for Heart Failure and Arrhythmia, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA
- Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH, USA
| | - Evelyn Thomas
- The Frick Center for Heart Failure and Arrhythmia, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA
- Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH, USA
| | - Shivangi Mohta
- The Frick Center for Heart Failure and Arrhythmia, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA
- Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH, USA
| | - Daniel Gratz
- The Frick Center for Heart Failure and Arrhythmia, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA
- Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH, USA
| | - Seth H. Weinberg
- The Frick Center for Heart Failure and Arrhythmia, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA
- Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH, USA
| | - Thomas J. Hund
- The Frick Center for Heart Failure and Arrhythmia, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA
- Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH, USA
- Department of Internal Medicine, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
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30
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Huang J, Liu Y, Chen JX, Lu XY, Zhu WJ, Qin L, Xun ZX, Zheng QY, Li EM, Sun N, Xu C, Chen HY. Harmine is an effective therapeutic small molecule for the treatment of cardiac hypertrophy. Acta Pharmacol Sin 2022; 43:50-63. [PMID: 33785860 PMCID: PMC8724320 DOI: 10.1038/s41401-021-00639-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 03/04/2021] [Indexed: 01/03/2023]
Abstract
Harmine is a β-carboline alkaloid isolated from Banisteria caapi and Peganum harmala L with various pharmacological activities, including antioxidant, anti-inflammatory, antitumor, anti-depressant, and anti-leishmanial capabilities. Nevertheless, the pharmacological effect of harmine on cardiomyocytes and heart muscle has not been reported. Here we found a protective effect of harmine on cardiac hypertrophy in spontaneously hypertensive rats in vivo. Further, harmine could inhibit the phenotypes of norepinephrine-induced hypertrophy in human embryonic stem cell-derived cardiomyocytes in vitro. It reduced the enlarged cell surface area, reversed the increased calcium handling and contractility, and downregulated expression of hypertrophy-related genes in norepinephrine-induced hypertrophy of human cardiomyocytes derived from embryonic stem cells. We further showed that one of the potential underlying mechanism by which harmine alleviates cardiac hypertrophy relied on inhibition of NF-κB phosphorylation and the stimulated inflammatory cytokines in pathological ventricular remodeling. Our data suggest that harmine is a promising therapeutic agent for cardiac hypertrophy independent of blood pressure modulation and could be a promising addition of current medications for cardiac hypertrophy.
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Affiliation(s)
- Jie Huang
- grid.8547.e0000 0001 0125 2443Department of Physiology and Pathophysiology, State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032 China
| | - Yang Liu
- grid.8547.e0000 0001 0125 2443Department of Echocardiography, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
| | - Jia-xin Chen
- grid.8547.e0000 0001 0125 2443Department of Physiology and Pathophysiology, State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032 China
| | - Xin-ya Lu
- grid.8547.e0000 0001 0125 2443Department of Physiology and Pathophysiology, State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032 China
| | - Wen-jia Zhu
- grid.8547.e0000 0001 0125 2443Department of Physiology and Pathophysiology, State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032 China
| | - Le Qin
- grid.8547.e0000 0001 0125 2443Department of Physiology and Pathophysiology, State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032 China
| | - Zi-xuan Xun
- grid.8547.e0000 0001 0125 2443Department of Physiology and Pathophysiology, State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032 China
| | - Qiu-yi Zheng
- grid.8547.e0000 0001 0125 2443Department of Physiology and Pathophysiology, State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032 China
| | - Er-min Li
- grid.8547.e0000 0001 0125 2443Department of Physiology and Pathophysiology, State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032 China
| | - Ning Sun
- grid.8547.e0000 0001 0125 2443Department of Physiology and Pathophysiology, State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032 China ,grid.411333.70000 0004 0407 2968Shanghai Key Lab of Birth Defect, Children’s Hospital of Fudan University, Shanghai, 201100 China ,grid.8547.e0000 0001 0125 2443Research Center on Aging and Medicine, Fudan University, Shanghai, 200032 China
| | - Chen Xu
- grid.8547.e0000 0001 0125 2443Department of Physiology and Pathophysiology, State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032 China
| | - Hai-yan Chen
- grid.8547.e0000 0001 0125 2443Department of Echocardiography, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
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Bu H, Ding Y, Li J, Zhu P, Shih YH, Wang M, Zhang Y, Lin X, Xu X. Inhibition of mTOR or MAPK ameliorates vmhcl/myh7 cardiomyopathy in zebrafish. JCI Insight 2021; 6:154215. [PMID: 34935644 PMCID: PMC8783688 DOI: 10.1172/jci.insight.154215] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 11/03/2021] [Indexed: 01/25/2023] Open
Abstract
Myosin heavy chain 7 (MYH7) is a major causative gene for hypertrophic cardiomyopathy, but the affected signaling pathways and therapeutics remain elusive. In this research, we identified ventricle myosin heavy chain like (vmhcl) as a zebrafish homolog of human MYH7, and we generated vmhcl frameshift mutants. We noted vmhcl-based embryonic cardiac dysfunction (VEC) in the vmhcl homozygous mutants and vmhcl-based adult cardiomyopathy (VAC) phenotypes in the vmhcl heterozygous mutants. Using the VEC model, we assessed 7 known cardiomyopathy signaling pathways pharmacologically and 11 candidate genes genetically via CRISPR/Cas9 genome editing technology based on microhomology-mediated end joining (MMEJ). Both studies converged on therapeutic benefits of mTOR or mitogen-activated protein kinase (MAPK) inhibition of VEC. While mTOR inhibition rescued the enlarged nuclear size of cardiomyocytes, MAPK inhibition restored the prolonged cell shape in the VEC model. The therapeutic effects of mTOR and MAPK inhibition were later validated in the VAC model. Together, vmhcl/myh7 loss of function is sufficient to induce cardiomyopathy in zebrafish. The VEC and VAC models in zebrafish are amenable to both efficient genetic and chemical genetic tools, offering a rapid in vivo platform for discovering candidate signaling pathways of MYH7 cardiomyopathy.
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Affiliation(s)
- Haisong Bu
- Department of Biochemistry and Molecular Biology, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA.,Department of Cardiothoracic Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Yonghe Ding
- Department of Biochemistry and Molecular Biology, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Jiarong Li
- Department of Biochemistry and Molecular Biology, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA.,Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Ping Zhu
- Department of Biochemistry and Molecular Biology, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Yu-Huan Shih
- Department of Biochemistry and Molecular Biology, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Mingmin Wang
- Department of Biochemistry and Molecular Biology, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA.,Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Yuji Zhang
- Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Xueying Lin
- Department of Biochemistry and Molecular Biology, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Xiaolei Xu
- Department of Biochemistry and Molecular Biology, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA
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Furkel J, Knoll M, Din S, Bogert NV, Seeger T, Frey N, Abdollahi A, Katus HA, Konstandin MH. C-MORE: A high-content single-cell morphology recognition methodology for liquid biopsies toward personalized cardiovascular medicine. Cell Rep Med 2021; 2:100436. [PMID: 34841289 PMCID: PMC8606902 DOI: 10.1016/j.xcrm.2021.100436] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 08/04/2021] [Accepted: 10/11/2021] [Indexed: 10/25/2022]
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33
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Du Y, Demillard LJ, Ren J. Catecholamine-induced cardiotoxicity: A critical element in the pathophysiology of stroke-induced heart injury. Life Sci 2021; 287:120106. [PMID: 34756930 DOI: 10.1016/j.lfs.2021.120106] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/24/2021] [Accepted: 10/26/2021] [Indexed: 01/20/2023]
Abstract
Cerebrovascular diseases such as ischemic stroke, brain hemorrhage, and subarachnoid hemorrhage provoke cardiac complications such as heart failure, neurogenic stress-related cardiomyopathy and Takotsubo cardiomyopathy. With regards to the pathophysiology of stroke-induced heart injury, several mechanisms have been postulated to contribute to this complex interaction between brain and heart, including damage from gut dysbiosis, immune and systematic inflammatory responses, microvesicle- and microRNA-mediated vascular injury and damage from a surge of catecholamines. All these cerebrovascular diseases may trigger pronounced catecholamine surges through diverse ways, including stimulation of hypothalamic-pituitary adrenal axis, dysregulation of autonomic system, and secretion of adrenocorticotropic hormone. Primary catecholamines involved in this pathophysiological response include norepinephrine (NE) and epinephrine. Both are important neurotransmitters that connect the nervous system with the heart, leading to cardiac damage via myocardial ischemia, calcium (Ca2+) overload, oxidative stress, and mitochondrial dysfunction. In this review, we will aim to summarize the molecular mechanisms behind catecholamine-induced cardiotoxicity including Ca2+ overload, oxidative stress, apoptosis, cardiac hypertrophy, interstitial fibrosis, and inflammation. In addition, we will focus on how synchronization among these pathways evokes cardiotoxicity.
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Affiliation(s)
- Yuxin Du
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China
| | - Laurie J Demillard
- School of Pharmacy, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA
| | - Jun Ren
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA.
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de Oliveira LS, Alborghetti MR, Carneiro RG, Bastos IMD, Amino R, Grellier P, Charneau S. Calcium in the Backstage of Malaria Parasite Biology. Front Cell Infect Microbiol 2021; 11:708834. [PMID: 34395314 PMCID: PMC8355824 DOI: 10.3389/fcimb.2021.708834] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 07/14/2021] [Indexed: 12/26/2022] Open
Abstract
The calcium ion (Ca2+) is a ubiquitous second messenger involved in key biological processes in prokaryotes and eukaryotes. In Plasmodium species, Ca2+ signaling plays a central role in the parasite life cycle. It has been associated with parasite development, fertilization, locomotion, and host cell infection. Despite the lack of a canonical inositol-1,4,5-triphosphate receptor gene in the Plasmodium genome, pharmacological evidence indicates that inositol-1,4,5-triphosphate triggers Ca2+ mobilization from the endoplasmic reticulum. Other structures such as acidocalcisomes, food vacuole and mitochondria are proposed to act as supplementary intracellular Ca2+ reservoirs. Several Ca2+-binding proteins (CaBPs) trigger downstream signaling. Other proteins with no EF-hand motifs, but apparently involved with CaBPs, are depicted as playing an important role in the erythrocyte invasion and egress. It is also proposed that a cross-talk among kinases, which are not members of the family of Ca2+-dependent protein kinases, such as protein kinases G, A and B, play additional roles mediated indirectly by Ca2+ regulation. This statement may be extended for proteins directly related to invasion or egress, such as SUB1, ERC, IMC1I, IMC1g, GAP45 and EBA175. In this review, we update our understanding of aspects of Ca2+-mediated signaling correlated to the developmental stages of the malaria parasite life cycle.
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Affiliation(s)
- Lucas Silva de Oliveira
- Laboratory of Biochemistry and Protein Chemistry, Department of Cell Biology, Institute of Biology, University of Brasilia, Brasilia, Brazil
- UMR 7245 MCAM, Molécules de Communication et Adaptation des Micro-organismes, Muséum National d’Histoire Naturelle, CNRS, Équipe Parasites et Protistes Libres, Paris, France
| | - Marcos Rodrigo Alborghetti
- Laboratory of Biochemistry and Protein Chemistry, Department of Cell Biology, Institute of Biology, University of Brasilia, Brasilia, Brazil
- Brazilian Biosciences National Laboratory, Brazilian Center for Research in Energy and Materials, Campinas, Brazil
| | - Renata Garcia Carneiro
- Laboratory of Biochemistry and Protein Chemistry, Department of Cell Biology, Institute of Biology, University of Brasilia, Brasilia, Brazil
| | - Izabela Marques Dourado Bastos
- Laboratory of Host-Pathogen Interaction, Department of Cell Biology, Institute of Biology, University of Brasilia, Brasilia, Brazil
| | - Rogerio Amino
- Unité Infection et Immunité Paludéennes, Institut Pasteur, Paris, France
| | - Philippe Grellier
- UMR 7245 MCAM, Molécules de Communication et Adaptation des Micro-organismes, Muséum National d’Histoire Naturelle, CNRS, Équipe Parasites et Protistes Libres, Paris, France
| | - Sébastien Charneau
- Laboratory of Biochemistry and Protein Chemistry, Department of Cell Biology, Institute of Biology, University of Brasilia, Brasilia, Brazil
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Li Y, Zhang Z, Li S, Yu T, Jia Z. Therapeutic Effects of Traditional Chinese Medicine on Cardiovascular Diseases: the Central Role of Calcium Signaling. Front Pharmacol 2021; 12:682273. [PMID: 34305595 PMCID: PMC8299363 DOI: 10.3389/fphar.2021.682273] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 06/01/2021] [Indexed: 12/18/2022] Open
Abstract
Calcium, as a second messenger, plays an important role in the pathogenesis of cardiovascular diseases (CVDs). The malfunction of calcium signaling in endothelial cells and vascular smooth muscle cells promotes hypertension. In cardiomyocytes, calcium overload induces apoptosis, leading to myocardial infarction and arrhythmias. Moreover, the calcium–calcineurin–nuclear factor of activated T cells (NFAT) pathway is essential for expressing the cardiac pro-hypertrophic gene. Heart failure is also characterized by reduced calcium transient amplitude and enhanced sarcoplasmic reticulum (SR) calcium leakage. Traditional Chinese medicine (TCM) has been used to treat CVDs for thousands of years in China. Because of its multicomponent and multitarget characteristics, TCM's unique advantages in CVD treatment are closely related to the modulation of multiple calcium handling proteins and calcium signaling pathways in different types of cells involved in distinct CVDs. Thus, we systematically review the diverse mechanisms of TCM in regulating calcium pathways to treat various types of CVDs, ranging from hypertrophic cardiomyopathy to diabetic heart disease.
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Affiliation(s)
- Yuxin Li
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Zhang Zhang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Sen Li
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Tingting Yu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Zhaoqi Jia
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
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Luo Y, Jiang N, May HI, Luo X, Ferdous A, Schiattarella GG, Chen G, Li Q, Li C, Rothermel BA, Jiang D, Lavandero S, Gillette TG, Hill JA. Cooperative Binding of ETS2 and NFAT Links Erk1/2 and Calcineurin Signaling in the Pathogenesis of Cardiac Hypertrophy. Circulation 2021; 144:34-51. [PMID: 33821668 PMCID: PMC8247545 DOI: 10.1161/circulationaha.120.052384] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 03/10/2021] [Indexed: 11/16/2022]
Abstract
BACKGROUND Cardiac hypertrophy is an independent risk factor for heart failure, a leading cause of morbidity and mortality globally. The calcineurin/NFAT (nuclear factor of activated T cells) pathway and the MAPK (mitogen-activated protein kinase)/Erk (extracellular signal-regulated kinase) pathway contribute to the pathogenesis of cardiac hypertrophy as an interdependent network of signaling cascades. How these pathways interact remains unclear and few direct targets responsible for the prohypertrophic role of NFAT have been described. METHODS By engineering cardiomyocyte-specific ETS2 (a member of the E26 transformation-specific sequence [ETS] domain family) knockout mice, we investigated the role of ETS2 in cardiac hypertrophy. Primary cardiomyocytes were used to evaluate ETS2 function in cell growth. RESULTS ETS2 is phosphorylated and activated by Erk1/2 on hypertrophic stimulation in both mouse (n=3) and human heart samples (n=8 to 19). Conditional deletion of ETS2 in mouse cardiomyocytes protects against pressure overload-induced cardiac hypertrophy (n=6 to 11). Silencing of ETS2 in the hearts of calcineurin transgenic mice significantly attenuates hypertrophic growth and contractile dysfunction (n=8). As a transcription factor, ETS2 is capable of binding to the promoters of hypertrophic marker genes, such as ANP, BNP, and Rcan1.4 (n=4). We report that ETS2 forms a complex with NFAT to stimulate transcriptional activity through increased NFAT binding to the promoters of at least 2 hypertrophy-stimulated genes: Rcan1.4 and microRNA-223 (=n4 to 6). Suppression of microRNA-223 in cardiomyocytes inhibits calcineurin-mediated cardiac hypertrophy (n=6), revealing microRNA-223 as a novel prohypertrophic target of the calcineurin/NFAT and Erk1/2-ETS2 pathways. CONCLUSIONS Our findings point to a critical role for ETS2 in calcineurin/NFAT pathway-driven cardiac hypertrophy and unveil a previously unknown molecular connection between the Erk1/2 activation of ETS2 and expression of NFAT/ETS2 target genes.
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Affiliation(s)
- Yuxuan Luo
- Departments of Internal Medicine, Cardiology Division (Y.L., N.J., H.I.M., X.L., A.F., G.G.S., G.C., Q.L., C.L., B.A.R., S.L., T.G.G., J.A.H.), University of Texas Southwestern Medical Center, Dallas
| | - Nan Jiang
- Departments of Internal Medicine, Cardiology Division (Y.L., N.J., H.I.M., X.L., A.F., G.G.S., G.C., Q.L., C.L., B.A.R., S.L., T.G.G., J.A.H.), University of Texas Southwestern Medical Center, Dallas
| | - Herman I. May
- Departments of Internal Medicine, Cardiology Division (Y.L., N.J., H.I.M., X.L., A.F., G.G.S., G.C., Q.L., C.L., B.A.R., S.L., T.G.G., J.A.H.), University of Texas Southwestern Medical Center, Dallas
| | - Xiang Luo
- Departments of Internal Medicine, Cardiology Division (Y.L., N.J., H.I.M., X.L., A.F., G.G.S., G.C., Q.L., C.L., B.A.R., S.L., T.G.G., J.A.H.), University of Texas Southwestern Medical Center, Dallas
- Molecular Biology (J.A.H.), University of Texas Southwestern Medical Center, Dallas
- Division of Cardiothoracic and Vascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (D.J.)
- Advanced Center for Chronic Diseases, Faculty of Chemical & Pharmaceutical Sciences and Faculty of Medicine, University of Chile, Santiago, Chile (S.L.)
- Corporacion Centro de Estudios Científicos de las Enfermedades Cronicas (CECEC), Santiago, Chile (S.L.)
| | - Anwarul Ferdous
- Departments of Internal Medicine, Cardiology Division (Y.L., N.J., H.I.M., X.L., A.F., G.G.S., G.C., Q.L., C.L., B.A.R., S.L., T.G.G., J.A.H.), University of Texas Southwestern Medical Center, Dallas
| | - Gabriele G. Schiattarella
- Departments of Internal Medicine, Cardiology Division (Y.L., N.J., H.I.M., X.L., A.F., G.G.S., G.C., Q.L., C.L., B.A.R., S.L., T.G.G., J.A.H.), University of Texas Southwestern Medical Center, Dallas
| | - Guihao Chen
- Departments of Internal Medicine, Cardiology Division (Y.L., N.J., H.I.M., X.L., A.F., G.G.S., G.C., Q.L., C.L., B.A.R., S.L., T.G.G., J.A.H.), University of Texas Southwestern Medical Center, Dallas
| | - Qinfeng Li
- Departments of Internal Medicine, Cardiology Division (Y.L., N.J., H.I.M., X.L., A.F., G.G.S., G.C., Q.L., C.L., B.A.R., S.L., T.G.G., J.A.H.), University of Texas Southwestern Medical Center, Dallas
| | - Chao Li
- Departments of Internal Medicine, Cardiology Division (Y.L., N.J., H.I.M., X.L., A.F., G.G.S., G.C., Q.L., C.L., B.A.R., S.L., T.G.G., J.A.H.), University of Texas Southwestern Medical Center, Dallas
| | - Beverly A. Rothermel
- Departments of Internal Medicine, Cardiology Division (Y.L., N.J., H.I.M., X.L., A.F., G.G.S., G.C., Q.L., C.L., B.A.R., S.L., T.G.G., J.A.H.), University of Texas Southwestern Medical Center, Dallas
| | - Dingsheng Jiang
- Division of Cardiothoracic and Vascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (D.J.)
| | - Sergio Lavandero
- Departments of Internal Medicine, Cardiology Division (Y.L., N.J., H.I.M., X.L., A.F., G.G.S., G.C., Q.L., C.L., B.A.R., S.L., T.G.G., J.A.H.), University of Texas Southwestern Medical Center, Dallas
- Advanced Center for Chronic Diseases, Faculty of Chemical & Pharmaceutical Sciences and Faculty of Medicine, University of Chile, Santiago, Chile (S.L.)
- Corporacion Centro de Estudios Científicos de las Enfermedades Cronicas (CECEC), Santiago, Chile (S.L.)
| | - Thomas G. Gillette
- Departments of Internal Medicine, Cardiology Division (Y.L., N.J., H.I.M., X.L., A.F., G.G.S., G.C., Q.L., C.L., B.A.R., S.L., T.G.G., J.A.H.), University of Texas Southwestern Medical Center, Dallas
| | - Joseph A. Hill
- Departments of Internal Medicine, Cardiology Division (Y.L., N.J., H.I.M., X.L., A.F., G.G.S., G.C., Q.L., C.L., B.A.R., S.L., T.G.G., J.A.H.), University of Texas Southwestern Medical Center, Dallas
- Molecular Biology (J.A.H.), University of Texas Southwestern Medical Center, Dallas
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Yu YD, Xiu YP, Li YF, Zhang J, Xue YT, Li Y. To Explore the Mechanism and Equivalent Molecular Group of Radix Astragali and Semen Lepidii in Treating Heart Failure Based on Network Pharmacology. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2021; 2021:5518192. [PMID: 34285700 PMCID: PMC8275399 DOI: 10.1155/2021/5518192] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 06/23/2021] [Accepted: 06/25/2021] [Indexed: 12/13/2022]
Abstract
Radix Astragali and Semen Lepidii (HQ-TLZ) is a commonly used herbal medicine combination for treatment of heart failure, which has a good clinical effect. However, its active components and mechanism of action are not clear, which limits its clinical application and development. In this study, we explored the mechanism of action of HQ-TLZ in the treatment of heart failure based on network pharmacology. We obtained 11 active ingredients and 109 targets from the TCMSP database and SwissTargetPrediction database. Next, we constructed the action network and carried out enrichment analysis. The results showed that HQ-TLZ treatment of heart failure is primarily achieved by regulating the insulin resistance, erbB signaling pathway, PI3K-Akt signaling pathway, and VEGF signaling pathway. After inverse targeting, molecular docking, and literature search, we determined that the equivalent molecular groups of HQ-TLZ in the treatment of heart failure were quercetin and kaempferol. Based on network pharmacology, we reveal the mechanism of action of HQ-TLZ in the treatment of heart failure to a certain extent. At the same time, we determined the composition of the equivalent molecular group. This provides a bridge for the consistency evaluation of natural herbs and molecular compounds, which is beneficial to the development of novel drugs and further research.
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Affiliation(s)
- Yi-ding Yu
- Shandong University of Traditional Chinese Medicine, Jinan 250014, China
| | - Yi-ping Xiu
- Shandong University of Traditional Chinese Medicine, Jinan 250014, China
| | - Yang-fan Li
- Shandong University of Traditional Chinese Medicine, Jinan 250014, China
| | - Juan Zhang
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250014, China
| | - Yi-tao Xue
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250014, China
| | - Yan Li
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250014, China
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38
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Guo Y, Yu ZY, Wu J, Gong H, Kesteven S, Iismaa SE, Chan AY, Holman S, Pinto S, Pironet A, Cox CD, Graham RM, Vennekens R, Feneley MP, Martinac B. The Ca 2+-activated cation channel TRPM4 is a positive regulator of pressure overload-induced cardiac hypertrophy. eLife 2021; 10:66582. [PMID: 34190686 PMCID: PMC8245133 DOI: 10.7554/elife.66582] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 06/20/2021] [Indexed: 01/19/2023] Open
Abstract
Pathological left ventricular hypertrophy (LVH) occurs in response to pressure overload and remains the single most important clinical predictor of cardiac mortality. The molecular pathways in the induction of pressure overload LVH are potential targets for therapeutic intervention. Current treatments aim to remove the pressure overload stimulus for LVH, but do not completely reverse adverse cardiac remodelling. Although numerous molecular signalling steps in the induction of LVH have been identified, the initial step by which mechanical stretch associated with cardiac pressure overload is converted into a chemical signal that initiates hypertrophic signalling remains unresolved. In this study, we show that selective deletion of transient receptor potential melastatin 4 (TRPM4) channels in mouse cardiomyocytes results in an approximately 50% reduction in the LVH induced by transverse aortic constriction. Our results suggest that TRPM4 channel is an important component of the mechanosensory signalling pathway that induces LVH in response to pressure overload and represents a potential novel therapeutic target for the prevention of pathological LVH.
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Affiliation(s)
- Yang Guo
- Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, Australia.,Cardiac Physiology and Transplantation Division, Victor Chang Cardiac Research Institute, Sydney, Australia.,St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - Ze-Yan Yu
- Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, Australia.,Cardiac Physiology and Transplantation Division, Victor Chang Cardiac Research Institute, Sydney, Australia.,St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - Jianxin Wu
- Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, Australia
| | - Hutao Gong
- Cardiac Physiology and Transplantation Division, Victor Chang Cardiac Research Institute, Sydney, Australia
| | - Scott Kesteven
- Cardiac Physiology and Transplantation Division, Victor Chang Cardiac Research Institute, Sydney, Australia.,St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - Siiri E Iismaa
- Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, Australia.,St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - Andrea Y Chan
- Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, Australia
| | - Sara Holman
- Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, Australia
| | - Silvia Pinto
- Laboratory of Ion Channel Research, Department of Molecular and Cellular Medicine, Katholieke Universiteit Leuven, Leuven, Belgium.,TRP Research Platform Leuven (TRPLe), Katholieke Universiteit Leuven, Leuven, Belgium
| | - Andy Pironet
- Laboratory of Ion Channel Research, Department of Molecular and Cellular Medicine, Katholieke Universiteit Leuven, Leuven, Belgium.,TRP Research Platform Leuven (TRPLe), Katholieke Universiteit Leuven, Leuven, Belgium
| | - Charles D Cox
- Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, Australia.,St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - Robert M Graham
- Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, Australia.,St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - Rudi Vennekens
- Laboratory of Ion Channel Research, Department of Molecular and Cellular Medicine, Katholieke Universiteit Leuven, Leuven, Belgium.,TRP Research Platform Leuven (TRPLe), Katholieke Universiteit Leuven, Leuven, Belgium
| | - Michael P Feneley
- Cardiac Physiology and Transplantation Division, Victor Chang Cardiac Research Institute, Sydney, Australia.,St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia.,Department of Cardiology, St Vincent's Hospital, Sydney, Australia
| | - Boris Martinac
- Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, Australia.,St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
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Kilian LS, Voran J, Frank D, Rangrez AY. RhoA: a dubious molecule in cardiac pathophysiology. J Biomed Sci 2021; 28:33. [PMID: 33906663 PMCID: PMC8080415 DOI: 10.1186/s12929-021-00730-w] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 04/23/2021] [Indexed: 02/08/2023] Open
Abstract
The Ras homolog gene family member A (RhoA) is the founding member of Rho GTPase superfamily originally studied in cancer cells where it was found to stimulate cell cycle progression and migration. RhoA acts as a master switch control of actin dynamics essential for maintaining cytoarchitecture of a cell. In the last two decades, however, RhoA has been coined and increasingly investigated as an essential molecule involved in signal transduction and regulation of gene transcription thereby affecting physiological functions such as cell division, survival, proliferation and migration. RhoA has been shown to play an important role in cardiac remodeling and cardiomyopathies; underlying mechanisms are however still poorly understood since the results derived from in vitro and in vivo experiments are still inconclusive. Interestingly its role in the development of cardiomyopathies or heart failure remains largely unclear due to anomalies in the current data available that indicate both cardioprotective and deleterious effects. In this review, we aimed to outline the molecular mechanisms of RhoA activation, to give an overview of its regulators, and the probable mechanisms of signal transduction leading to RhoA activation and induction of downstream effector pathways and corresponding cellular responses in cardiac (patho)physiology. Furthermore, we discuss the existing studies assessing the presented results and shedding light on the often-ambiguous data. Overall, we provide an update of the molecular, physiological and pathological functions of RhoA in the heart and its potential in cardiac therapeutics.
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Affiliation(s)
- Lucia Sophie Kilian
- Department of Internal Medicine III (Cardiology, Angiology, Intensive Care), University Medical Center Kiel, Rosalind-Franklin Str. 12, 24105, Kiel, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 24105, Kiel, Germany
| | - Jakob Voran
- Department of Internal Medicine III (Cardiology, Angiology, Intensive Care), University Medical Center Kiel, Rosalind-Franklin Str. 12, 24105, Kiel, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 24105, Kiel, Germany
| | - Derk Frank
- Department of Internal Medicine III (Cardiology, Angiology, Intensive Care), University Medical Center Kiel, Rosalind-Franklin Str. 12, 24105, Kiel, Germany. .,DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 24105, Kiel, Germany.
| | - Ashraf Yusuf Rangrez
- Department of Internal Medicine III (Cardiology, Angiology, Intensive Care), University Medical Center Kiel, Rosalind-Franklin Str. 12, 24105, Kiel, Germany. .,DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 24105, Kiel, Germany. .,Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
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40
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Maternal diet high in linoleic acid alters offspring fatty acids and cardiovascular function in a rat model. Br J Nutr 2021; 127:540-553. [PMID: 33858529 DOI: 10.1017/s0007114521001276] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Linoleic acid (LA), an essential n-6 fatty acid (FA), is critical for fetal development. We investigated the effects of maternal high LA (HLA) diet on offspring cardiac development and its relationship to circulating FA and cardiovascular function in adolescent offspring, and the ability of the postnatal diet to reverse any adverse effects. Female Wistar Kyoto rats were fed low LA (LLA; 1·44 % energy from LA) or high LA (HLA; 6·21 % energy from LA) diets for 10 weeks before pregnancy and during gestation/lactation. Offspring, weaned at postnatal day 25, were fed LLA or HLA diets and euthanised at postnatal day 40 (n 6-8). Maternal HLA diet decreased circulating total cholesterol and HDL-cholesterol in females and decreased total plasma n-3 FA in males, while maternal and postnatal HLA diets decreased total plasma n-3 FA in females. α-Linolenic acid (ALA) and EPA were decreased by postnatal but not maternal HLA diets in both sexes. Maternal and postnatal HLA diets increased total plasma n-6 and LA, and a maternal HLA diet increased circulating leptin, in both male and female offspring. Maternal HLA decreased slopes of systolic and diastolic pressure-volume relationship (PVR), and increased cardiac Col1a1, Col3a1, Atp2a1 and Notch1 in males. Maternal and postnatal HLA diets left-shifted the diastolic PVR in female offspring. Coronary reactivity was altered in females, with differential effects on flow repayment after occlusion. Thus, maternal HLA diets impact lipids, FA and cardiac function in offspring, with postnatal diet modifying FA and cardiac function in the female offspring.
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41
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Tamarit J, Britti E, Delaspre F, Medina-Carbonero M, Sanz-Alcázar A, Cabiscol E, Ros J. Mitochondrial iron and calcium homeostasis in Friedreich ataxia. IUBMB Life 2021; 73:543-553. [PMID: 33675183 DOI: 10.1002/iub.2457] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 02/08/2021] [Accepted: 02/08/2021] [Indexed: 12/13/2022]
Abstract
Friedreich Ataxia is a neuro-cardiodegenerative disease caused by the deficiency of frataxin, a mitochondrial protein. Many evidences indicate that frataxin deficiency causes an unbalance of iron homeostasis. Nevertheless, in the last decade many results also highlighted the importance of calcium unbalance in the deleterious downstream effects caused by frataxin deficiency. In this review, the role of these two metals has been gathered to give a whole view of how iron and calcium dyshomeostasys impacts on cellular functions and, as a result, which strategies can be followed to find an effective therapy for the disease.
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Affiliation(s)
- Jordi Tamarit
- Dept. Ciències Mèdiques Bàsiques, Universitat de Lleida, IRBLleida, Lleida, Spain
| | - Elena Britti
- Dept. Ciències Mèdiques Bàsiques, Universitat de Lleida, IRBLleida, Lleida, Spain
| | - Fabien Delaspre
- Dept. Ciències Mèdiques Bàsiques, Universitat de Lleida, IRBLleida, Lleida, Spain
| | | | - Arabela Sanz-Alcázar
- Dept. Ciències Mèdiques Bàsiques, Universitat de Lleida, IRBLleida, Lleida, Spain
| | - Elisa Cabiscol
- Dept. Ciències Mèdiques Bàsiques, Universitat de Lleida, IRBLleida, Lleida, Spain
| | - Joaquim Ros
- Dept. Ciències Mèdiques Bàsiques, Universitat de Lleida, IRBLleida, Lleida, Spain
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Yu ZY, Gong H, Wu J, Dai Y, Kesteven SH, Fatkin D, Martinac B, Graham RM, Feneley MP. Cardiac Gq Receptors and Calcineurin Activation Are Not Required for the Hypertrophic Response to Mechanical Left Ventricular Pressure Overload. Front Cell Dev Biol 2021; 9:639509. [PMID: 33659256 PMCID: PMC7917224 DOI: 10.3389/fcell.2021.639509] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 01/26/2021] [Indexed: 01/19/2023] Open
Abstract
Rationale Gq-coupled receptors are thought to play a critical role in the induction of left ventricular hypertrophy (LVH) secondary to pressure overload, although mechano-sensitive channel activation by a variety of mechanisms has also been proposed, and the relative importance of calcineurin- and calmodulin kinase II (CaMKII)-dependent hypertrophic pathways remains controversial. Objective To determine the mechanisms regulating the induction of LVH in response to mechanical pressure overload. Methods and Results Transgenic mice with cardiac-targeted inhibition of Gq-coupled receptors (GqI mice) and their non-transgenic littermates (NTL) were subjected to neurohumoral stimulation (continuous, subcutaneous angiotensin II (AngII) infusion for 14 days) or mechanical pressure overload (transverse aortic arch constriction (TAC) for 21 days) to induce LVH. Candidate signaling pathway activation was examined. As expected, LVH observed in NTL mice with AngII infusion was attenuated in heterozygous (GqI+/-) mice and absent in homozygous (GqI-/-) mice. In contrast, LVH due to TAC was unaltered by either heterozygous or homozygous Gq inhibition. Gene expression of atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and α-skeletal actin (α-SA) was increased 48 h after AngII infusion or TAC in NTL mice; in GqI mice, the increases in ANP, BNP and α-SA in response to AngII were completely absent, as expected, but all three increased after TAC. Increased nuclear translocation of nuclear factor of activated T-cells c4 (NFATc4), indicating calcineurin pathway activation, occurred in NTL mice with AngII infusion but not TAC, and was prevented in GqI mice infused with AngII. Nuclear and cytoplasmic CaMKIIδ levels increased in both NTL and GqI mice after TAC but not AngII infusion, with increased cytoplasmic phospho- and total histone deacetylase 4 (HDAC4) and increased nuclear myocyte enhancer factor 2 (MEF2) levels. Conclusion Cardiac Gq receptors and calcineurin activation are required for neurohumorally mediated LVH but not for LVH induced by mechanical pressure overload (TAC). Rather, TAC-induced LVH is associated with activation of the CaMKII-HDAC4-MEF2 pathway.
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Affiliation(s)
- Ze-Yan Yu
- Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.,Cardiology Department, St Vincent's Hospital, Darlinghurst, NSW, Australia.,Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - Hutao Gong
- Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia
| | - Jianxin Wu
- Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia
| | - Yun Dai
- Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia
| | - Scott H Kesteven
- Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia
| | - Diane Fatkin
- Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.,Cardiology Department, St Vincent's Hospital, Darlinghurst, NSW, Australia.,Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - Boris Martinac
- Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.,Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - Robert M Graham
- Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.,Cardiology Department, St Vincent's Hospital, Darlinghurst, NSW, Australia.,Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - Michael P Feneley
- Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.,Cardiology Department, St Vincent's Hospital, Darlinghurst, NSW, Australia.,Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
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Bollmann P, Werner F, Jaron M, Bruns TA, Wache H, Runte J, Boknik P, Kirchhefer U, Müller FU, Buchwalow IB, Rothemund S, Neumann J, Gergs U. Initial Characterization of Stressed Transgenic Mice With Cardiomyocyte-Specific Overexpression of Protein Phosphatase 2C. Front Pharmacol 2021; 11:591773. [PMID: 33597873 PMCID: PMC7883593 DOI: 10.3389/fphar.2020.591773] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 12/07/2020] [Indexed: 12/17/2022] Open
Abstract
As part of our ongoing studies on the potential pathophysiological role of serine/threonine phosphatases (PP) in the mammalian heart, we have generated mice with cardiac-specific overexpression of PP2Cβ (PP2C-TG) and compared them with littermate wild type mice (WT) serving as a control. Cardiac fibrosis was noted histologically in PP2C-TG. Collagen 1a, interleukin-6 and the natriuretic peptides ANP and BNP were augmented in PP2C-TG vs. WT (p < 0.05). Left atrial preparations from PP2C-TG were less resistant to hypoxia than atria from WT. PP2C-TG maintained cardiac function after the injection of lipopolysaccharide (LPS, a model of sepsis) and chronic isoproterenol treatment (a model of heart failure) better than WT. Crossbreeding of PP2C-TG mice with PP2A-TG mice (a genetic model of heart failure) resulted in double transgenic (DT) mice that exhibited a pronounced increase of heart weight in contrast to the mild hypertrophy noted in the mono-transgenic mice. The ejection fraction was reduced in PP2C-TG and in PP2A-TG mice compared with WT, but the reduction was the highest in DT compared with WT. PP2A enzyme activity was enhanced in PP2A-TG and DT mice compared with WT and PP2C-TG mice. In summary, cardiac overexpression of PP2Cβ and co-overexpression of both the catalytic subunit of PP2A and PP2Cβ were detrimental to cardiac function. PP2Cβ overexpression made cardiac preparations less resistant to hypoxia than WT, leading to fibrosis, but PP2Cβ overexpression led to better adaptation to some stressors, such as LPS or chronic β-adrenergic stimulation. Hence, the effect of PP2Cβ is context sensitive.
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Affiliation(s)
- Paula Bollmann
- Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany
| | - Franziska Werner
- Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany
| | - Marko Jaron
- Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany
| | - Tom A Bruns
- Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany
| | - Hartmut Wache
- Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany
| | - Jochen Runte
- Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany
| | - Peter Boknik
- Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Westfälische Wilhelms-Universität, Münster, Germany
| | - Uwe Kirchhefer
- Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Westfälische Wilhelms-Universität, Münster, Germany
| | - Frank U Müller
- Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Westfälische Wilhelms-Universität, Münster, Germany
| | | | | | - Joachim Neumann
- Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany
| | - Ulrich Gergs
- Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany
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Lambert K, Demion M, Lagacé JC, Hokayem M, Dass M, Virsolvy A, Jover B, bourret A, Bisbal C. Grape polyphenols and exercise training have distinct molecular effects on cardiac hypertrophy in a model of obese insulin-resistant rats. J Nutr Biochem 2021; 87:108522. [DOI: 10.1016/j.jnutbio.2020.108522] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 08/25/2020] [Accepted: 09/30/2020] [Indexed: 01/02/2023]
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Trypanosoma cruzi Modulates PIWI-Interacting RNA Expression in Primary Human Cardiac Myocytes during the Early Phase of Infection. Int J Mol Sci 2020; 21:ijms21249439. [PMID: 33322418 PMCID: PMC7764157 DOI: 10.3390/ijms21249439] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 11/28/2020] [Accepted: 12/10/2020] [Indexed: 02/07/2023] Open
Abstract
Trypanosoma cruzi dysregulates the gene expression profile of primary human cardiomyocytes (PHCM) during the early phase of infection through a mechanism which remains to be elucidated. The role that small non-coding RNAs (sncRNA) including PIWI-interacting RNA (piRNA) play in regulating gene expression during the early phase of infection is unknown. To understand how T. cruzi dysregulate gene expression in the heart, we challenged PHCM with T. cruzi trypomastigotes and analyzed sncRNA, especially piRNA, by RNA-sequencing. The parasite induced significant differential expression of host piRNAs, which can target and regulate the genes which are important during the early infection phase. An average of 21,595,866 (88.40%) of clean reads mapped to the human reference genome. The parasite induced 217 unique piRNAs that were significantly differentially expressed (q ≥ 0.8). Of these differentially expressed piRNAs, 6 were known and 211 were novel piRNAs. In silico analysis showed that some of the dysregulated known and novel piRNAs could target and potentially regulate the expression of genes including NFATC2, FOS and TGF-β1, reported to play important roles during T. cruzi infection. Further evaluation of the specific functions of the piRNAs in the regulation of gene expression during the early phase of infection will enhance our understanding of the molecular mechanism of T. cruzi pathogenesis. Our novel findings constitute the first report that T. cruzi can induce differential expression of piRNAs in PHCM, advancing our knowledge about the involvement of piRNAs in an infectious disease model, which can be exploited for biomarker and therapeutic development.
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Takano APC, Senger N, Barreto-Chaves MLM. The endocrinological component and signaling pathways associated to cardiac hypertrophy. Mol Cell Endocrinol 2020; 518:110972. [PMID: 32777452 DOI: 10.1016/j.mce.2020.110972] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Revised: 07/14/2020] [Accepted: 07/30/2020] [Indexed: 02/06/2023]
Abstract
Although myocardial growth corresponds to an adaptive response to maintain cardiac contractile function, the cardiac hypertrophy is a condition that occurs in many cardiovascular diseases and typically precedes the onset of heart failure. Different endocrine factors such as thyroid hormones, insulin, insulin-like growth factor 1 (IGF-1), angiotensin II (Ang II), endothelin (ET-1), catecholamines, estrogen, among others represent important stimuli to cardiomyocyte hypertrophy. Thus, numerous endocrine disorders manifested as changes in the local environment or multiple organ systems are especially important in the context of progression from cardiac hypertrophy to heart failure. Based on that information, this review summarizes experimental findings regarding the influence of such hormones upon signalling pathways associated with cardiac hypertrophy. Understanding mechanisms through which hormones differentially regulate cardiac hypertrophy could open ways to obtain therapeutic approaches that contribute to prevent or delay the onset of heart failure related to endocrine diseases.
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Affiliation(s)
| | - Nathalia Senger
- Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil
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Xu W, Jain MK, Zhang L. Molecular link between circadian clocks and cardiac function: a network of core clock, slave clock, and effectors. Curr Opin Pharmacol 2020; 57:28-40. [PMID: 33189913 DOI: 10.1016/j.coph.2020.10.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 09/27/2020] [Accepted: 10/06/2020] [Indexed: 02/08/2023]
Abstract
The circadian rhythm has a strong influence on both cardiac physiology and disease in humans. Preclinical studies primarily using tissue-specific transgenic mouse models have contributed to our understanding of the molecular mechanism of the circadian clock in the cardiovascular system. The core clock driven by CLOCK:BMAL1 complex functions as a universal timing machinery that primarily sets the pace in all mammalian cell types. In one specific cell or tissue type, core clock may control a secondary transcriptional oscillator, conceptualized as slave clock, which confers the oscillatory expression of tissue-specific effectors. Here, we discuss a core clock-slave clock-effectors network, which links the molecular clock to cardiac function.
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Affiliation(s)
- Weiyi Xu
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Mukesh K Jain
- Case Cardiovascular Research Institute, Department of Medicine, Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, USA; School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA
| | - Lilei Zhang
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
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Zhang DH, Zhang JL, Huang Z, Wu LM, Wang ZM, Li YP, Tian XY, Kong LY, Yao R, Zhang YZ. Deubiquitinase Ubiquitin-Specific Protease 10 Deficiency Regulates Sirt6 signaling and Exacerbates Cardiac Hypertrophy. J Am Heart Assoc 2020; 9:e017751. [PMID: 33170082 PMCID: PMC7763723 DOI: 10.1161/jaha.120.017751] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Background Cardiac hypertrophy (CH) is a physiological response that compensates for blood pressure overload. Under pathological conditions, hypertrophy can progress to heart failure as a consequence of the disorganized growth of cardiomyocytes and cardiac tissue. USP10 (ubiquitin‐specific protease 10) is a member of the ubiquitin‐specific protease family of cysteine proteases, which are involved in viral infection, oxidative stress, lipid drop formation, and heat shock. However, the role of USP10 in CH remains largely unclear. Here, we investigated the roles of USP10 in CH. Methods and Results Cardiac‐specific USP10 knockout (USP10‐CKO) mice and USP10‐transgenic (USP10‐TG) mice were used to examined the role of USP10 in CH following aortic banding. The specific functions of USP10 were further examined in isolated cardiomyocytes. USP10 expression was increased in murine hypertrophic hearts following aortic banding and in isolated cardiomyocytes in response to hypertrophic agonist. Mice deficient in USP10 in the heart exhibited exaggerated cardiac hypertrophy and fibrosis following pressure overload stress, which resulted in worsening of cardiac contractile function. In contrast, cardiac overexpression of USP10 protected against pressure overload‐induced maladaptive CH. Mechanistically, we demonstrated that USP10 activation and interaction with Sirt6 in response to angiotensin II led to a marked increase in the ubiquitination of Sirt6 and resulted in Akt signaling downregulation and attenuation of cardiomyocyte hypertrophy. Accordingly, inactivation of USP10 reduced Sirt6 abundance and stability and diminished Sirt6‐induced downstream signaling in cardiomyocytes. Conclusions USP10 functions as a Sirt6 deubiquitinase that induces cardiac myocyte hypertrophy and triggers maladaptive CH.
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Affiliation(s)
- Dian-Hong Zhang
- Cardiovascular Hospital the First Affiliated Hospital of Zhengzhou University Zhengzhou University Zhengzhou China
| | - Jie-Lei Zhang
- Department of Endocrinology the First Affiliated Hospital of Zhengzhou University Zhengzhou University Zhengzhou China
| | - Zhen Huang
- Cardiovascular Hospital the First Affiliated Hospital of Zhengzhou University Zhengzhou University Zhengzhou China
| | - Lei-Ming Wu
- Cardiovascular Hospital the First Affiliated Hospital of Zhengzhou University Zhengzhou University Zhengzhou China
| | - Zhong-Min Wang
- Department of Cardiology FuWai Central China Cardiovascular Hospital Zhengzhou China
| | - Ya-Peng Li
- Cardiovascular Hospital the First Affiliated Hospital of Zhengzhou University Zhengzhou University Zhengzhou China
| | - Xin-Yu Tian
- Cardiovascular Hospital the First Affiliated Hospital of Zhengzhou University Zhengzhou University Zhengzhou China
| | - Ling-Yao Kong
- Cardiovascular Hospital the First Affiliated Hospital of Zhengzhou University Zhengzhou University Zhengzhou China
| | - Rui Yao
- Cardiovascular Hospital the First Affiliated Hospital of Zhengzhou University Zhengzhou University Zhengzhou China
| | - Yan-Zhou Zhang
- Cardiovascular Hospital the First Affiliated Hospital of Zhengzhou University Zhengzhou University Zhengzhou China
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Cardiac CaMKII δ and Wenxin Keli Prevents Ang II-Induced Cardiomyocyte Hypertrophy by Modulating CnA-NFATc4 and Inflammatory Signaling Pathways in H9c2 Cells. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:9502651. [PMID: 33149757 PMCID: PMC7603598 DOI: 10.1155/2020/9502651] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 08/18/2020] [Accepted: 09/20/2020] [Indexed: 01/23/2023]
Abstract
Previous studies have demonstrated that calcium-/calmodulin-dependent protein kinase II (CaMKII) and calcineurin A-nuclear factor of activated T-cell (CnA-NFAT) signaling pathways play key roles in cardiac hypertrophy (CH). However, the interaction between CaMKII and CnA-NFAT signaling remains unclear. H9c2 cells were cultured and treated with angiotensin II (Ang II) with or without silenced CaMKIIδ (siCaMKII) and cyclosporine A (CsA, a calcineurin inhibitor) and subsequently treated with Wenxin Keli (WXKL). Patch clamp recording was conducted to assess L-type Ca2+ current (ICa-L), and the expression of proteins involved in signaling pathways was measured by western blotting. Myocardial cytoskeletal protein and nuclear translocation of target proteins were assessed by immunofluorescence. The results indicated that siCaMKII suppressed Ang II-induced CH, as evidenced by reduced cell surface area and ICa-L. Notably, siCaMKII inhibited Ang II-induced activation of CnA and NFATc4 nuclear transfer. Inflammatory signaling was inhibited by siCaMKII and WXKL. Interestingly, CsA inhibited CnA-NFAT pathway expression but activated CaMKII signaling. In conclusion, siCaMKII may improve CH, possibly by blocking CnA-NFAT and MyD88 signaling, and WXKL has a similar effect. These data suggest that inhibiting CaMKII, but not CnA, may be a promising approach to attenuate CH and arrhythmia progression.
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50
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Kaur N, Raja R, Ruiz-Velasco A, Liu W. Cellular Protein Quality Control in Diabetic Cardiomyopathy: From Bench to Bedside. Front Cardiovasc Med 2020; 7:585309. [PMID: 33195472 PMCID: PMC7593653 DOI: 10.3389/fcvm.2020.585309] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 09/09/2020] [Indexed: 12/14/2022] Open
Abstract
Heart failure is a serious comorbidity and the most common cause of mortality in diabetes patients. Diabetic cardiomyopathy (DCM) features impaired cellular structure and function, culminating in heart failure; however, there is a dearth of specific clinical therapy for treating DCM. Protein homeostasis is pivotal for the maintenance of cellular viability under physiological and pathological conditions, particularly in the irreplaceable cardiomyocytes; therefore, it is tightly regulated by a protein quality control (PQC) system. Three evolutionarily conserved molecular processes, the unfolded protein response (UPR), the ubiquitin-proteasome system (UPS), and autophagy, enhance protein turnover and preserve protein homeostasis by suppressing protein translation, degrading misfolded or unfolded proteins in cytosol or organelles, disposing of damaged and toxic proteins, recycling essential amino acids, and eliminating insoluble protein aggregates. In response to increased cellular protein demand under pathological insults, including the diabetic condition, a coordinated PQC system retains cardiac protein homeostasis and heart performance, on the contrary, inappropriate PQC function exaggerates cardiac proteotoxicity with subsequent heart dysfunction. Further investigation of the PQC mechanisms in diabetes propels a more comprehensive understanding of the molecular pathogenesis of DCM and opens new prospective treatment strategies for heart disease and heart failure in diabetes patients. In this review, the function and regulation of cardiac PQC machinery in diabetes mellitus, and the therapeutic potential for the diabetic heart are discussed.
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Affiliation(s)
- Namrita Kaur
- Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester, United Kingdom
| | - Rida Raja
- Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester, United Kingdom
| | - Andrea Ruiz-Velasco
- Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester, United Kingdom
| | - Wei Liu
- Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester, United Kingdom
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