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Zhang D, Li G, Liu X, Wang Y, Wu J, Ren Y, She G, Zheng D, Zhao Y, Deng XL, Li M, Zhao L. K Ca3.1 upregulation mediated by Ang II-induced JNK/AP-1 activation contributes to atrial fibrosis. Cell Signal 2025; 131:111731. [PMID: 40064281 DOI: 10.1016/j.cellsig.2025.111731] [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: 11/29/2024] [Revised: 02/27/2025] [Accepted: 03/07/2025] [Indexed: 03/15/2025]
Abstract
Atrial fibrillation is strongly associated with an increased risk of embolism, stroke, and heart failure. Current therapeutic approaches often have limited efficacy, and controlling atrial fibrosis remains a critical objective for upstream therapies. The specific mechanisms driving atrial fibrosis remain incompletely understood. The intermediate-conductance calcium-activated potassium channel KCa3.1 has been implicated in promoting fibroblast activation in various fibrotic diseases. This study investigates the role of angiotensin II (Ang II) in regulating KCa3.1, as well as its involvement in the pathogenesis of atrial fibrosis and the underlying signaling mechanisms. In a rat model, chronic Ang II infusion for 4 weeks induced atrial fibrosis, which was significantly attenuated by TRAM-34, a specific KCa3.1 channel blocker. In cultured rat atrial fibroblasts, Ang II treatment promoted fibroblast differentiation, proliferation, migration and collagen production, effects that were suppressed by TRAM-34 and KCa3.1 knockdown. Overexpression of KCa3.1 in fibroblasts further confirmed its pro-fibrotic role. Mechanistically, Ang II upregulated KCa3.1 expression and current density by activating the JNK/AP-1 signaling pathway. This involved phosphorylation of JNK, c-Jun, and c-Fos, leading to the formation of c-Jun/c-Fos heterodimers that directly bound to the KCa3.1 promoter to enhance its transcription. Together, these findings demonstrate that KCa3.1 mediates fibroblast activation and atrial fibrosis through the JNK/AP-1 pathway.
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Affiliation(s)
- Dongmei Zhang
- Department of Pathology and Pathophysiology, Suzhou Medical College of Soochow University, 199 Ren-ai Road, Suzhou 215123, Jiangsu, China
| | - Guangyao Li
- Department of Pathology and Pathophysiology, Suzhou Medical College of Soochow University, 199 Ren-ai Road, Suzhou 215123, Jiangsu, China
| | - Xiang Liu
- Department of Pathology and Pathophysiology, Suzhou Medical College of Soochow University, 199 Ren-ai Road, Suzhou 215123, Jiangsu, China
| | - Yan Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an 710061, Shaanxi, China
| | - Jie Wu
- Department of Pathology and Pathophysiology, Suzhou Medical College of Soochow University, 199 Ren-ai Road, Suzhou 215123, Jiangsu, China
| | - Yujie Ren
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an 710061, Shaanxi, China
| | - Gang She
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an 710061, Shaanxi, China
| | - Dong Zheng
- Department of Pathology and Pathophysiology, Suzhou Medical College of Soochow University, 199 Ren-ai Road, Suzhou 215123, Jiangsu, China
| | - Yinxia Zhao
- Central Laboratory, Shanghai Xuhui Central Hospital, 366 North Longchuan Road, Shanghai 200031, China
| | - Xiu-Ling Deng
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an 710061, Shaanxi, China
| | - Min Li
- Institute of Biology and Medical Sciences, Soochow University, 199 Ren-ai Road, Suzhou 215123, Jiangsu, China.
| | - Limei Zhao
- Department of Pathology and Pathophysiology, Suzhou Medical College of Soochow University, 199 Ren-ai Road, Suzhou 215123, Jiangsu, China; MOE Key Laboratory of Geriatric Diseases and Immunology, School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou 215123, Jiangsu, China.
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Pisani LF, Albertini Petroni G, Crespi G, Mola S, Annunziata ML, Caprioli FA, Porta C, Pastorelli L. Lower Expression of SARS-CoV-2 Host Cell Entry Genes in the Intestinal Mucosa of IBD Patients With Quiescent or Mildly Active Disease. Inflamm Bowel Dis 2025; 31:1690-1701. [PMID: 40279370 DOI: 10.1093/ibd/izaf079] [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: 12/31/2024] [Indexed: 04/27/2025]
Abstract
BACKGROUND Long-term immunosuppressive therapy typically increases the risk of viral infection, yet during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, inflammatory bowel disease (IBD) patients showed reduced severe coronavirus disease 2019 (COVID-19) susceptibility. This suggests potential overlapping molecular mechanisms between IBD and COVID-19 that warrant investigation. METHODS From April 2020 to April 2022, we enrolled 363 IBD patients and 146 healthy donors. Serum samples were analyzed by enzyme-linked immunoadsorption assay to determine the presence of anti-SARS-CoV-2 antibodies and to measure concentrations of the host-soluble factors sACE2 and mannose-binding lectin (MBL), which have SARS-CoV-2 neutralizing activity. Furthermore, colonic mucosa biopsies were analyzed by real-time PCR to confirm the upregulation of MBL2 as well as to assess the expression of genes encoding SARS-CoV-2 entry molecules (ie, ACE2, TMPRSS2, TMPRSS4, ADAM17, AGTR1). RESULTS Intestinal mucosa expression of ACE2, TMPRSS2, and TMPRSS4 genes was significantly lower in IBD than in healthy individuals, regardless of the type of medication, while ADAM17 and AGT1R were similar across groups. Serum sACE2 levels changed minimally, whereas circulating MBL levels were significantly higher in CD and somewhat elevated in UC patients versus controls. Parallel trends in MBL2 gene expression were observed in IBD patients' intestinal mucosa. CONCLUSIONS Overall, our study indicates that the presence of higher basal circulating levels of MBL in CD patients and the decreased intestinal mucosa expression of the SARS-CoV-2 receptor ACE2 and the host cell priming proteases TMPRSS2 and TMPRSS4 in both CD and UC patients may reduce COVID-19 risk, underscoring the potential protective role of these biomarkers in IBD populations against SARS-CoV-2 infection.
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Affiliation(s)
- Laura Francesca Pisani
- Unit of Immunology and Functional Genomics, Centro Cardiologico Monzino IRCCS, Milan, Italy
| | | | - Giorgia Crespi
- Department of Pharmaceutical Sciences, University of Piemonte Orientale, Novara, Italy
- Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, Novara, Italy
| | - Silvia Mola
- Department of Pharmaceutical Sciences, University of Piemonte Orientale, Novara, Italy
- Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, Novara, Italy
| | - Maria Laura Annunziata
- Gastroenterology and Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | - Flavio Andrea Caprioli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Chiara Porta
- Department of Pharmaceutical Sciences, University of Piemonte Orientale, Novara, Italy
- Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, Novara, Italy
| | - Luca Pastorelli
- Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
- Liver and Gastroenterology Unit, ASST Santi Paolo e Carlo, Milan, Italy
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Upadhyay PK, Thakur N, Vishwakarma VK, Chaurasiya HS, Ansari TM. Modulation of Angiotensin-II and Angiotensin 1-7 Levels Influences Cardiac Function in Myocardial Ischemia-reperfusion Injury. Curr Drug Res Rev 2025; 17:102-112. [PMID: 38299413 DOI: 10.2174/0125899775280160240122065607] [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: 09/26/2023] [Revised: 12/11/2023] [Accepted: 01/16/2024] [Indexed: 02/02/2024]
Abstract
The angiotensin-converting enzyme-2 (ACE-2) alters the pathophysiology of various fatal cardiovascular diseases, including ischemic heart disease, whereas angiotensin 1-7 (Ang 1-7) exerts a wide range of actions. The effects of ischemia-reperfusion (IR) injury include damage to myocardial tissue that initiates protease action, causing cardiac cell death. Angiotensin- II (Ang-II) contributes through the renin-angiotensin system (RAS) to the IR injury, whereas Ang 1-7 paradoxically exerts a protective effect through the same. Thus, the myocardial ischemic reperfusion injury (MIRI) may be altered by the RAS of the heart. This review paper focuses on ACE-2, angiotensin-converting enzyme (ACE), and Ang 1-7 regulation in the RAS of the heart in the pathophysiology of MIRI. The treatment in such conditions using ACE-2 activator, ACE inhibitor, and Ang-II antagonists may promote vascular functions as well as cardio- protection.
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Affiliation(s)
- Prabhat Kumar Upadhyay
- Institute of Pharmaceutical Research, GLA University, Mathura, 281406, Uttar Pradesh, India
| | - Navneet Thakur
- Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India
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Zheng J, Hao H. Targeting renal damage: The ACE2/Ang-(1-7)/mas axis in chronic kidney disease. Cell Signal 2024; 124:111413. [PMID: 39293746 DOI: 10.1016/j.cellsig.2024.111413] [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: 06/28/2024] [Revised: 09/08/2024] [Accepted: 09/11/2024] [Indexed: 09/20/2024]
Abstract
The renin-angiotensin system (RAS) is a crucial factor in chronic kidney disease (CKD) progression, affecting renal function and contributing significantly to renal tissue inflammation and fibrosis. Activation of the classical ACE/Ang II/AT1 axis exacerbates renal damage, while the ACE2/Ang-(1-7)/Mas axis has shown promise in reducing CKD progression in numerous animal models. Recently, the ACE2/Ang-(1-7)/Mas axis has emerged as a promising target for CKD interventions. This review provides a comprehensive review of the pivotal role of this axis in CKD pathogenesis and systematically examines various molecules and pharmaceutical agents targeting this pathway. This review aims to elucidate potential strategies for delaying or halting CKD progression, offering patients more effective treatment options.
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Affiliation(s)
- Jian Zheng
- Department of Pathology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai 200090, PR China
| | - Hua Hao
- Department of Pathology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai 200090, PR China.
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Ruan Y, Yu Y, Wu M, Jiang Y, Qiu Y, Ruan S. The renin-angiotensin-aldosterone system: An old tree sprouts new shoots. Cell Signal 2024; 124:111426. [PMID: 39306263 DOI: 10.1016/j.cellsig.2024.111426] [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: 06/30/2024] [Revised: 08/25/2024] [Accepted: 09/17/2024] [Indexed: 09/27/2024]
Abstract
The intricate physiological and pathological diversity of the Renin-Angiotensin-Aldosterone System (RAAS) underpins its role in maintaining bodily equilibrium. This paper delves into the classical axis (Renin-ACE-Ang II-AT1R axis), the protective arm (ACE2-Ang (1-7)-MasR axis), the prorenin-PRR-MAP kinases ERK1/2 axis, and the Ang IV-AT4R-IRAP cascade of RAAS, examining their functions in both physiological and pathological states. The dysregulation or hyperactivation of RAAS is intricately linked to numerous diseases, including cardiovascular disease (CVD), renal damage, metabolic disease, eye disease, Gastrointestinal disease, nervous system and reproductive system diseases. This paper explores the pathological mechanisms of RAAS in detail, highlighting its significant role in disease progression. Currently, in addition to traditional drugs like ACEI, ARB, and MRA, several novel therapeutics have emerged, such as angiotensin receptor-enkephalinase inhibitors, nonsteroidal mineralocorticoid receptor antagonists, aldosterone synthase inhibitors, aminopeptidase A inhibitors, and angiotensinogen inhibitors. These have shown potential efficacy and application prospects in various clinical trials for related diseases. Through an in-depth analysis of RAAS, this paper aims to provide crucial insights into its complex physiological and pathological mechanisms and offer valuable guidance for developing new therapeutic approaches. This comprehensive discussion is expected to advance the RAAS research field and provide innovative ideas and directions for future clinical treatment strategies.
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Affiliation(s)
- Yaqing Ruan
- The Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou 350004, China; Fujian University of Traditional Chinese Medicine, Fuzhou 350000, China
| | - Yongxin Yu
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Meiqin Wu
- The Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou 350004, China; Fujian University of Traditional Chinese Medicine, Fuzhou 350000, China
| | - Yulang Jiang
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yuliang Qiu
- The Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou 350004, China; Fujian University of Traditional Chinese Medicine, Fuzhou 350000, China.
| | - Shiwei Ruan
- The Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou 350004, China; Fujian University of Traditional Chinese Medicine, Fuzhou 350000, China.
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Zhu T, Ye Z, Song J, Zhang J, Zhao Y, Xu F, Wang J, Huang X, Gao B, Li F. Effect of extracellular matrix stiffness on efficacy of Dapagliflozin for diabetic cardiomyopathy. Cardiovasc Diabetol 2024; 23:273. [PMID: 39049086 PMCID: PMC11270890 DOI: 10.1186/s12933-024-02369-x] [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: 02/06/2024] [Accepted: 07/18/2024] [Indexed: 07/27/2024] Open
Abstract
BACKGROUND Extracellular matrix (ECM) stiffness is closely related to the progress of diabetic cardiomyopathy (DCM) and the response of treatment of DCM to anti-diabetic drugs. Dapagliflozin (Dapa) has been proven to have cardio-protective efficacy for diabetes and listed as the first-line drug to treat heart failure. But the regulatory relationship between ECM stiffness and treatment efficacy of Dapa remains elusive. MATERIALS AND METHODS This work investigated the effect of ECM stiffness on DCM progression and Dapa efficacy using both in vivo DCM rat model and in vitro myocardial cell model with high glucose injury. First, through DCM rat models with various levels of myocardial injury and administration with Dapa treatment for four weeks, the levels of myocardial injury, myocardial oxidative stress, expressions of AT1R (a mechanical signal protein) and the stiffness of myocardial tissues were obtained. Then for mimicking the stiffness of myocardial tissues at early and late stages of DCM, we constructed cell models through culturing H9c2 myocardial cells on the polyacrylamide gels with two stiffness and exposed to a high glucose level and without/with Dapa intervention. The cell viability, reactive oxygen species (ROS) levels and expressions of mechanical signal sensitive proteins were obtained. RESULTS The DCM progression is accompanied by the increased myocardial tissue stiffness, which can synergistically exacerbate myocardial cell injury with high glucose. Dapa can improve the ECM stiffness-induced DCM progression and its efficacy on DCM is more pronounced on the soft ECM, which is related to the regulation pathway of AT1R-FAK-NOX2. Besides, Dapa can inhibit the expression of the ECM-induced integrin β1, but without significant impact on piezo 1. CONCLUSIONS Our study found the regulation and effect of biomechanics in the DCM progression and on the Dapa efficacy on DCM, providing the new insights for the DCM treatment. Additionally, our work showed the better clinical prognosis of DCM under early Dapa intervention.
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Affiliation(s)
- Tong Zhu
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, P.R. China
- Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, 710049, P.R. China
- Department of Cardiovasology, Xidian Group Hospital, Xi'an, 710077, P.R. China
| | - Zhaoyang Ye
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, P.R. China
- Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, 710049, P.R. China
| | - Jingjing Song
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, P.R. China
- Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, 710049, P.R. China
| | - Junjie Zhang
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, P.R. China
- Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, 710049, P.R. China
| | - Yuxiang Zhao
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, P.R. China
- Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, 710049, P.R. China
| | - Feng Xu
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, P.R. China
- Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, 710049, P.R. China
| | - Jun Wang
- Department of Health Evaluation and Promotion, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
| | - Xin Huang
- Department of Cardiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
| | - Bin Gao
- Department of Endocrinology, Tangdu Hospital, Air Force Military Medical University, Xi'an, 710032, P.R. China.
| | - Fei Li
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, P.R. China.
- Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, 710049, P.R. China.
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Xie L, Zang D, Yang J, Xue F, Sui W, Zhang Y. Combination of ADAM17 knockdown with eplerenone is more effective than single therapy in ameliorating diabetic cardiomyopathy. Front Pharmacol 2024; 15:1364827. [PMID: 38799171 PMCID: PMC11122002 DOI: 10.3389/fphar.2024.1364827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 03/20/2024] [Indexed: 05/29/2024] Open
Abstract
Background The renin-angiotensin-aldosterone system (RAAS) members, especially Ang II and aldosterone, play key roles in the pathogenesis of diabetic cardiomyopathy (DCM). Angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers combined with aldosterone receptor antagonists (mineralocorticoid receptor antagonists) have substantially improved clinical outcomes in patients with DCM. However, the use of the combination has been limited due to its high risk of inducing hyperkalemia. Methods Type 1 diabetes was induced in 8-week-old male C57BL/6J mice by intraperitoneal injection of streptozotocin at a dose of 55 mg/kg for 5 consecutive days. Adeno-associated virus 9-mediated short-hairpin RNA (shRNA) was used to knock down the expression of ADAM17 in mice hearts. Eplerenone was administered via gavage at 200 mg/kg daily for 4 weeks. Primary cardiac fibroblasts were exposed to high glucose (HG) in vitro for 24 h to examine the cardiac fibroblasts to myofibroblasts transformation (CMT). Results Cardiac collagen deposition and CMT increased in diabetic mice, leading to cardiac fibrosis and dysfunction. In addition, ADAM17 expression and activity increased in the hearts of diabetic mice. ADAM17 inhibition and eplerenone treatment both improved diabetes-induced cardiac fibrosis, cardiac hypertrophy and cardiac dysfunction, ADAM17 deficiency combined with eplerenone further reduced the effects of cardiac fibrosis, cardiac hypertrophy and cardiac dysfunction compared with single therapy in vivo. High-glucose stimulation promotes CMT in vitro and leads to increased ADAM17 expression and activity. ADAM17 knockdown and eplerenone pretreatment can reduce the CMT of fibroblasts that is induced by high glucose levels by inhibiting TGFβ1/Smad3 activation; the combination of the two can further reduce CMT compared with single therapy in vitro. Conclusion Our findings indicated that ADAM17 knockout could improve diabetes-induced cardiac dysfunction and remodeling through the inhibition of RAAS overactivation when combined with eplerenone treatment, which reduced TGF-β1/Smad3 pathway activation-mediated CMT. The combined intervention of ADAM17 deficiency and eplerenone therapy provided additional cardiac protection compared with a single therapy alone without disturbing potassium level. Therefore, the combination of ADAM17 inhibition and eplerenone is a potential therapeutic strategy for human DCM.
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Affiliation(s)
- Lin Xie
- National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Dejin Zang
- National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Jianmin Yang
- National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Fei Xue
- National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Wenhai Sui
- National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Yun Zhang
- National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
- Cardiovascular Disease Research Center of Shandong First Medical University, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
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Kuo TC, Hsu WL, Wu VC, Jan TR, Tsai PSJ, Lee YJ. Urinary angiotensin-converting enzyme 2 and its activity in cats with chronic kidney disease. Front Vet Sci 2024; 11:1362379. [PMID: 38756510 PMCID: PMC11097973 DOI: 10.3389/fvets.2024.1362379] [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: 12/28/2023] [Accepted: 04/17/2024] [Indexed: 05/18/2024] Open
Abstract
Introduction Angiotensin-converting enzyme 2 (ACE2) played an important role in the renin-angiotensin-aldosterone system (RAAS) and it was proved to be renoprotective in renal disease. Urinary angiotensin-converting enzyme 2 (uACE2) has been shown to reflect renal injury in human and experimental studies, but its role in feline kidney disease remains unknown. Aims Our objectives involve comparing uACE2 concentrations and activities in cats across CKD stages with healthy controls, investigating the relationship between uACE2 concentrations, activities, and clinicopathological data in feline CKD patients, and assessing the predictive abilities of both for CKD progression. Methods A retrospective, case-control study. The concentration and activity of uACE2 were measured by commercial ELISA and fluorometric assay kits, respectively. The concentration was adjusted to give uACE2 concentration-to-creatinine ratios (UACCRs). Results In total, 67 cats consisting of 24 control and 43 chronic kidney disease (CKD), including 24 early-stage CKD and 19 late-stage CKD, were enrolled in this study. UACCR values were significantly higher in both early-stage (2.100 [1.142-4.242] x 10-6) and late-stage feline CKD (4.343 [2.992-5.0.71] x 10-6) compared to healthy controls (0.894 [0.610-1.076] x 10-6; p < 0.001), and there was also significant difference between-early stage group and late-stage group (p = 0.026). Urinary ACE2 activity (UAA) was significantly lower in CKD cats (1.338 [0.644-2.755] x pmol/min/ml) compared to the healthy cats (7.989 [3.711-15.903] x pmol/min/ml; p < 0.001). UACCR demonstrated an independent, positive correlation with BUN (p < 0.001), and UAA exhibited an independent, negative correlation with plasma creatinine (p < 0.001). Both UACCR and UAA did not yield significant results in predicting CKD progression based on the ROC curve analysis. Conclusion and clinical importance uACE2 concentration and activity exhibit varying changes as renal function declines, particularly in advanced CKD cats.
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Affiliation(s)
- Tzu-Chien Kuo
- Institute of Veterinary Clinical Science, School of Veterinary Medicine, College of Bio-Resources and Agriculture, National Taiwan University, Taipei, Taiwan
| | - Wei-Li Hsu
- Graduate Institute of Microbiology and Public Health, College of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Vin-Cent Wu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Tong-Rong Jan
- Department of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan
| | - Pei-Shiue Jason Tsai
- Department of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan
| | - Ya-Jane Lee
- Institute of Veterinary Clinical Science, School of Veterinary Medicine, College of Bio-Resources and Agriculture, National Taiwan University, Taipei, Taiwan
- National Taiwan University Veterinary Hospital, College of Bio-Resources and Agriculture, National Taiwan University, Taipei, Taiwan
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Zhao H, Li Z, Yan M, Ma L, Dong X, Li X, Zhang H, Li P. Irbesartan ameliorates diabetic kidney injury in db/db mice by restoring circadian rhythm and cell cycle. J Transl Int Med 2024; 12:157-169. [PMID: 38799791 PMCID: PMC11117442 DOI: 10.2478/jtim-2022-0049] [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] [Indexed: 05/29/2024] Open
Abstract
Background and Objectives Irbesartan has been widely used in the clinical treatment of diabetic kidney disease (DKD). However, the molecular mechanism of its delay of DKD disease progression has not been fully elucidated. The aim of the present study was to investigate the mechanism of irbesartan in the treatment of DKD. Materials and Methods C57BL/KsJ db/db mice were randomly divided into the model group and irbesartan-treated group. After treatment with irbesartan for 12 weeks, the effects on blood glucose, body weight, 24-h urinary albumin, and renal injuries were evaluated. Microarray was used to determine the differentially expressed genes (DEGs) in the renal cortex of mice. |Log FC| <0.5 and false discovery rate (FDR) <0.25 were set as the screening criteria. Kyoto Encyclopedia of Genes and Genomes (KEGG), gene ontology (GO), protein-protein interaction (PPI) network and modules, and microRNA (miRNA)-DEGs network analysis were applied to analyze the DEGs. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the results of microarray. Results The present study demonstrated irbesartan could significantly improve the renal function in db/db mice through decreasing 24-h urinary albumin and alleviating the pathological injury of kidney. Irbesartan may affect the expression of numerous kidney genes involved in circadian rhythm, cell cycle, micoRNAs in cancer, and PI3K-AKT signaling pathway. In the miRNA-DEGs network, miR-1970, miR-703, miR-466f, miR-5135, and miR-132-3p were the potential targets for irbesartan treatment. The validation test confirmed that key genes regulating circadian rhythm (Arntl, Per3, and Dbp) and cell cycle (Prc1, Ccna2, and Ccnb2) were restored in db/db mice on treatment with Irbesartan. Conclusion Generally, irbesartan can effectively treat DKD by regulating the circadian rhythm and cell cycle. The DEGs and pathways identified in the study will provide new insights into the potential mechanisms of irbesartan in the treatment of DKD.
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Affiliation(s)
- Hailing Zhao
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China–Japan Friendship Hospital, Beijing100029, China
| | - Zhiguo Li
- The Hebei Key Lab for Organ Fibrosis, the Hebei Key Lab for Chronic Disease, School of Public Health, International Science and Technology Cooperation Base of Geriatric Medicine, North China University of Science and Technology, Tangshan063210, Hebei Province, China
| | - Meihua Yan
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China–Japan Friendship Hospital, Beijing100029, China
| | - Liang Ma
- Clinical Laboratory, China–Japan Friendship Hospital, Beijing10029, China
| | - Xi Dong
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China–Japan Friendship Hospital, Beijing100029, China
| | - Xin Li
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China–Japan Friendship Hospital, Beijing100029, China
| | - Haojun Zhang
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China–Japan Friendship Hospital, Beijing100029, China
| | - Ping Li
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China–Japan Friendship Hospital, Beijing100029, China
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10
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Zhao H, Li Z, Yan M, Ma L, Dong X, Li X, Zhang H, Li P. Irbesartan ameliorates diabetic kidney injury in db/db mice by restoring circadian rhythm and cell cycle. J Transl Int Med 2024; 12:157-169. [PMID: 38779121 PMCID: PMC11107183 DOI: 10.2478/jtim-2023-0049] [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] [Indexed: 05/25/2024] Open
Abstract
Background and Objectives Irbesartan has been widely used in the clinical treatment of diabetic kidney disease (DKD). However, the molecular mechanism of its delay of DKD disease progression has not been fully elucidated. The aim of the present study was to investigate the mechanism of irbesartan in the treatment of DKD. Materials and Methods C57BL/KsJ db/db mice were randomly divided into the model group and irbesartan-treated group. After treatment with irbesartan for 12 weeks, the effects on blood glucose, body weight, 24-h urinary albumin, and renal injuries were evaluated. Microarray was used to determine the differentially expressed genes (DEGs) in the renal cortex of mice. |Log FC| <0.5 and false discovery rate (FDR) <0.25 were set as the screening criteria. Kyoto Encyclopedia of Genes and Genomes (KEGG), gene ontology (GO), protein-protein interaction (PPI) network and modules, and microRNA (miRNA)-DEGs network analysis were applied to analyze the DEGs. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the results of microarray. Results The present study demonstrated irbesartan could significantly improve the renal function in db/db mice through decreasing 24-h urinary albumin and alleviating the pathological injury of kidney. Irbesartan may affect the expression of numerous kidney genes involved in circadian rhythm, cell cycle, micoRNAs in cancer, and PI3K-AKT signaling pathway. In the miRNA-DEGs network, miR-1970, miR-703, miR-466f, miR-5135, and miR-132-3p were the potential targets for irbesartan treatment. The validation test confirmed that key genes regulating circadian rhythm (Arntl, Per3, and Dbp) and cell cycle (Prc1, Ccna2, and Ccnb2) were restored in db/db mice on treatment with Irbesartan. Conclusion Generally, irbesartan can effectively treat DKD by regulating the circadian rhythm and cell cycle. The DEGs and pathways identified in the study will provide new insights into the potential mechanisms of irbesartan in the treatment of DKD.
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Affiliation(s)
- Hailing Zhao
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China–Japan Friendship Hospital, Beijing100029, China
| | - Zhiguo Li
- The Hebei Key Lab for Organ Fibrosis, the Hebei Key Lab for Chronic Disease, School of Public Health, International Science and Technology Cooperation Base of Geriatric Medicine, North China University of Science and Technology, Tangshan063210, Hebei Province, China
| | - Meihua Yan
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China–Japan Friendship Hospital, Beijing100029, China
| | - Liang Ma
- Clinical Laboratory, China–Japan Friendship Hospital, Beijing10029, China
| | - Xi Dong
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China–Japan Friendship Hospital, Beijing100029, China
| | - Xin Li
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China–Japan Friendship Hospital, Beijing100029, China
| | - Haojun Zhang
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China–Japan Friendship Hospital, Beijing100029, China
| | - Ping Li
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China–Japan Friendship Hospital, Beijing100029, China
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11
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Osorio-Llanes E, Castellar-López J, Rosales W, Montoya Y, Bustamante J, Zalaquett R, Bravo-Sagua R, Riquelme JA, Sánchez G, Chiong M, Lavandero S, Mendoza-Torres E. Novel Strategies to Improve the Cardioprotective Effects of Cardioplegia. Curr Cardiol Rev 2024; 20:CCR-EPUB-137763. [PMID: 38275069 PMCID: PMC11071679 DOI: 10.2174/011573403x263956231129064455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 09/17/2023] [Accepted: 10/20/2023] [Indexed: 01/27/2024] Open
Abstract
The use of cardioprotective strategies as adjuvants of cardioplegic solutions has become an ideal alternative for the improvement of post-surgery heart recovery. The choice of the optimal cardioplegia, as well as its distribution mechanism, remains controversial in the field of cardiovascular surgery. There is still a need to search for new and better cardioprotective methods during cardioplegic procedures. New techniques for the management of cardiovascular complications during cardioplegia have evolved with new alternatives and additives, and each new strategy provides a tool to neutralize the damage after ischemia/reperfusion events. Researchers and clinicians have committed themselves to studying the effect of new strategies and adjuvant components with the potential to improve the cardioprotective effect of cardioplegic solutions in preventing myocardial ischemia/reperfusion-induced injury during cardiac surgery. The aim of this review is to explore the different types of cardioplegia, their protection mechanisms, and which strategies have been proposed to enhance the function of these solutions in hearts exposed to cardiovascular pathologies that require surgical alternatives for their corrective progression.
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Affiliation(s)
- Estefanie Osorio-Llanes
- Faculty of Exact and Natural Sciences, Grupo de Investigación Avanzada en Biomedicina, Universidad Libre Barranquilla, Atlantico, Colombia
| | - Jairo Castellar-López
- Faculty of Exact and Natural Sciences, Grupo de Investigación Avanzada en Biomedicina, Universidad Libre Barranquilla, Atlantico, Colombia
| | - Wendy Rosales
- Faculty of Exact and Natural Sciences, Grupo de Investigación Avanzada en Biomedicina, Universidad Libre Barranquilla, Atlantico, Colombia
| | - Yuliet Montoya
- Grupo de Dinámica Cardiovascular (GDC), Escuela de Ciencias de la Salud, Universidad Pontificia Bolivariana, Medellin, Colombia
| | - John Bustamante
- Grupo de Dinámica Cardiovascular (GDC), Escuela de Ciencias de la Salud, Universidad Pontificia Bolivariana, Medellin, Colombia
| | - Ricardo Zalaquett
- Department of Cardiovascular Diseases, Faculty of Medicine, Universidad Finis Terrae - Clínica Las Condes, Santiago, Chile
| | - Roberto Bravo-Sagua
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences & Faculty of Medicine, Universidad de Chile, Santiago, Chile
- Laboratorio OMEGA, INTA, University of Chile, Santiago, Chile
| | - Jaime A. Riquelme
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences & Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Gina Sánchez
- Physiopathology Program, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Santiago, Chile
| | - Mario Chiong
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences & Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Sergio Lavandero
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences & Faculty of Medicine, Universidad de Chile, Santiago, Chile
- Department of Internal Medicine (Cardiology Division), University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Evelyn Mendoza-Torres
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences & Faculty of Medicine, Universidad de Chile, Santiago, Chile
- Faculty of Health Sciences, Grupo de Investigación Avanzada en Biomedicina, Universidad Libre Seccional Barranquilla, Barranquilla, Colombia
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12
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Zhang J, Su R, Wang Y, Wang H, Li S, Yang X, Liu G. Protective effect of small extracellular vesicles (EVs) derived from ACE2-modified human umbilical cord mesenchymal stem cells against renal ischemia-reperfusion injury. Nephrology (Carlton) 2024; 29:5-17. [PMID: 37667547 DOI: 10.1111/nep.14237] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 07/27/2023] [Accepted: 08/13/2023] [Indexed: 09/06/2023]
Abstract
AIM Acute kidney injury is a severe disease that is closely associated with substantial morbidity and mortality. The most common cause of AKI is renal ischemia-reperfusion injury. Mesenchymal stem cells (MSCs) have previously been shown to have renoprotective effects. However, extracellular vesicles secreted by MSCs are thought to be the key for the therapeutic effects of MSCs. This study investigated whether small EVs derived from ACE2-modified human umbilical cord MSCs could alleviate RIRI and explored their underlying molecular mechanisms METHODS: A lentivirus carrying an ACE2 overexpression vector was constructed and used to infect MSCs. The small EVs were isolated from MSC-conditioned medium by ultracentrifugation. HK-2 cells were cocultured with MSC-ACE2-EVs and subjected to hypoxia/reoxygenation injury. MSCs-ACE2-EVs were injected into RIRI mice. Biochemical and morphological characteristics were assessed, and the levels of inflammatory-related factors, oxidative stress products, and apoptosis in HK-2 cells and kidney tissues were assessed RESULTS: In vitro, MSC-ACE2-EVs had stronger anti-inflammatory, antioxidative stress, and antiapoptotic effects in HK-2 cells subjected to H/R than MSC-NC-EVs. In vivo, MSC-ACE2-EVs could target the injured kidney, reduce blood creatinine and urea nitrogen levels, and protect the kidney from I/R, and this effect may have been related to the activation of the Nrf2/HO-1 signalling pathway CONCLUSION: Taken together, our results demonstrated the anti-inflammatory, antioxidative stress, and antiapoptotic effects of MSC-ACE2-EVs, which protected against I/R injury in vitro and vivo. MSC-ACE2-EVs may be therapeutic agents for RIRI.
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Affiliation(s)
- Jiaying Zhang
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Jinan, China
- Key Laboratory of Reproductive Endocrinology of the Ministry of Education, Shandong University, Jinan, China
| | - Rongyun Su
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Jinan, China
- Key Laboratory of Reproductive Endocrinology of the Ministry of Education, Shandong University, Jinan, China
| | - Yinghui Wang
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Jinan, China
- Key Laboratory of Reproductive Endocrinology of the Ministry of Education, Shandong University, Jinan, China
| | - Honggang Wang
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Jinan, China
- Key Laboratory of Reproductive Endocrinology of the Ministry of Education, Shandong University, Jinan, China
| | - Shan Li
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Jinan, China
- Key Laboratory of Reproductive Endocrinology of the Ministry of Education, Shandong University, Jinan, China
| | - Xue Yang
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Jinan, China
- Key Laboratory of Reproductive Endocrinology of the Ministry of Education, Shandong University, Jinan, China
| | - Gang Liu
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Jinan, China
- Key Laboratory of Reproductive Endocrinology of the Ministry of Education, Shandong University, Jinan, China
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13
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Abreu MAD, de Castro PASV, Moreira FRC, de Oliveira Ferreira H, Simões E Silva AC. Potential Role of Novel Cardiovascular Biomarkers in Pediatric Patients with Chronic Kidney Disease. Mini Rev Med Chem 2024; 24:491-506. [PMID: 37231748 DOI: 10.2174/1389557523666230523114331] [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: 02/23/2023] [Revised: 04/15/2023] [Accepted: 04/26/2023] [Indexed: 05/27/2023]
Abstract
BACKGROUND Cardiovascular Disease is the leading cause of death in adult and pediatric patients with Chronic Kidney Disease (CKD) and its pathogenesis involves the interaction of multiple pathways. As Inflammatory mechanisms play a critical role in the vascular disease of CKD pediatric patients, there are several biomarkers related to inflammation strongly associated with this comorbidity. OBJECTIVE This review provides available evidence on the link between several biomarkers and the pathophysiology of heart disease in patients with CKD. METHODS The data were obtained independently by the authors, who carried out a comprehensive and non-systematic search in PubMed, Cochrane, Scopus, and SciELO databases. The search terms were "Chronic Kidney Disease", "Cardiovascular Disease", "Pediatrics", "Pathophysiology", "Mineral and Bone Disorder (MBD)", "Renin Angiotensin System (RAS)", "Biomarkers", "BNP", "NTproBNP", "CK-MB", "CXCL6", "CXCL16", "Endocan-1 (ESM-1)", "FABP3", "FABP4", h-FABP", "Oncostatin- M (OSM)", "Placental Growth Factor (PlGF)" and "Troponin I". RESULTS The pathogenesis of CKD-mediated cardiovascular disease is linked to inflammatory biomarkers, which play a critical role in the initiation, maintenance, and progression of cardiovascular disease. There are several biomarkers associated with cardiovascular disease in pediatric patients, including BNP, NTproBNP, CK-MB, CXCL6, CXCL16, Endocan-1 (ESM-1), FABP3, FABP4, Oncostatin- M (OSM), Placental Growth Factor (PlGF), and Troponin I. CONCLUSION The pathogenesis of CKD-mediated cardiovascular disease is not completely understood, but it is linked to inflammatory biomarkers. Further studies are required to elucidate the pathophysiological and potential role of these novel biomarkers.
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Affiliation(s)
- Maria Augusta Duarte Abreu
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil
| | - Pedro Alves Soares Vaz de Castro
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil
| | - Fernanda Rocha Chaves Moreira
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil
| | - Henrique de Oliveira Ferreira
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil
| | - Ana Cristina Simões E Silva
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil
- Department of Pediatric Unit of Pediatric Nephrology, Faculty of Medicine UFMG, Belo Horizonte, Minas Gerais, Brazil
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14
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de Miranda AS, Macedo DS, Rocha NP, Teixeira AL. Targeting the Renin-Angiotensin System (RAS) for Neuropsychiatric Disorders. Curr Neuropharmacol 2024; 22:107-122. [PMID: 36173067 PMCID: PMC10716884 DOI: 10.2174/1570159x20666220927093815] [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: 04/24/2022] [Revised: 07/03/2022] [Accepted: 08/14/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Neuropsychiatric disorders, such as mood disorders, schizophrenia, and Alzheimer's disease (AD) and related dementias, are associated to significant morbidity and mortality worldwide. The pathophysiological mechanisms of neuropsychiatric disorders remain to be fully elucidated, which has hampered the development of effective therapies. The Renin Angiotensin System (RAS) is classically viewed as a key regulator of cardiovascular and renal homeostasis. The discovery that RAS components are expressed in the brain pointed out a potential role for this system in central nervous system (CNS) pathologies. The understanding of RAS involvement in the pathogenesis of neuropsychiatric disorders may contribute to identifying novel therapeutic targets. AIMS We aim to report current experimental and clinical evidence on the role of RAS in physiology and pathophysiology of mood disorders, schizophrenia, AD and related dementias. We also aim to discuss bottlenecks and future perspectives that can foster the development of new related therapeutic strategies. CONCLUSION The available evidence supports positive therapeutic effects for neuropsychiatric disorders with the inhibition/antagonism of the ACE/Ang II/AT1 receptor axis or the activation of the ACE2/Ang-(1-7)/Mas receptor axis. Most of this evidence comes from pre-clinical studies and clinical studies lag much behind, hampering a potential translation into clinical practice.
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Affiliation(s)
- Aline Silva de Miranda
- Interdisciplinary Laboratory of Medical Investigation (LIIM), Faculty of Medicine, UFMG, Belo Horizonte, MG, Brazil
- Department of Morphology, Laboratory of Neurobiology, Biological Science Institute, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Danielle S Macedo
- Department of Physiology and Pharmacology, Neuropharmacology Laboratory, Drug Research, and Development Center, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - Natalia P Rocha
- Department of Neurology, The Mitchell Center for Alzheimer's Disease and Related Brain Disorders, McGovern Medical School, University of Texas Health Science Center at Houston, TX, USA
| | - Antonio L Teixeira
- Department of Psychiatry and Behavioral Sciences, Neuropsychiatry Program, McGovern Medical School, University of Texas Health Science Center at Houston, TX, USA
- Faculdade Santa Casa BH, Belo Horizonte, Brasil
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15
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Hao F, Li Y, Zhang Y, Han Y, Shang J, Gan L, Zheng J, Zhang C. Inhibition of USP1 ameliorates hypertensive nephropathy through regulating oxidative stress and ferroptosis: A precise treatment via SJB3-019A nanodelivery. Eur J Pharm Biopharm 2023; 193:187-197. [PMID: 37949326 DOI: 10.1016/j.ejpb.2023.11.009] [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: 08/04/2023] [Revised: 10/23/2023] [Accepted: 11/07/2023] [Indexed: 11/12/2023]
Abstract
Hypertensive nephropathy is second only to diabetes for the causation of chronic kidney disease worldwide. As the mortality and morbidity of hypertensive nephropathy keep increasing, it is important to elucidate its pathogenesis and develop new treatment strategies. In this study, an angiotensin II (Ang II)-induced renal cell system was established, and the expression of ubiquitin specific peptidase 1 (USP1) in human kidney (HK-2) cells was found to be regulated by Ang II treatment through quantitative RT-PCR and Western blot assay. The detection of glutathione peroxidase (GSH-Px), malondialdehyde (MDA) and lipid reactive oxygen species (ROS) levels revealed that interference with USP1 reversed Ang II-induced oxidative stress and ferroptosis, which was enhanced by overexpression of USP1. Subsequently, USP1 inhibitor SJB3-019A loaded in MIL-100 and PEGTK was modified to fabricate SJB3-019A@MIL-PEGTK nanoparticles, which was confirmed to exhibit excellent alleviation of hypertension-induced oxidative stress and ferroptosis in renal cells both in vitro and in vivo. Our study identified an important pathogenesis of hypertensive nephropathy and SJB3-019A@MIL-PEGTK nanoparticle was used to develop an effective clinical treatment for hypertensive nephropathy.
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Affiliation(s)
- Fangyi Hao
- Department 1, Nephrology, Heilongjiang Academy of Traditional Chinese Medicine, Harbin 150000, China
| | - Ying Li
- Department 1, Nephrology, Heilongjiang Academy of Traditional Chinese Medicine, Harbin 150000, China
| | - Yunzhu Zhang
- Department 1, Nephrology, Heilongjiang Academy of Traditional Chinese Medicine, Harbin 150000, China
| | - Yangwenxuan Han
- Department 1, Nephrology, Heilongjiang Academy of Traditional Chinese Medicine, Harbin 150000, China
| | - Jing Shang
- Department 1, Nephrology, Heilongjiang Academy of Traditional Chinese Medicine, Harbin 150000, China
| | - Lu Gan
- Department 1, Nephrology, Heilongjiang Academy of Traditional Chinese Medicine, Harbin 150000, China
| | - Jiaxin Zheng
- Department 2, Nephrology, Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150000, China.
| | - Chunjian Zhang
- Department 1, Nephrology, Heilongjiang Academy of Traditional Chinese Medicine, Harbin 150000, China.
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16
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Dow LF, Case AM, Paustian MP, Pinkerton BR, Simeon P, Trippier PC. The evolution of small molecule enzyme activators. RSC Med Chem 2023; 14:2206-2230. [PMID: 37974956 PMCID: PMC10650962 DOI: 10.1039/d3md00399j] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 09/20/2023] [Indexed: 11/19/2023] Open
Abstract
There is a myriad of enzymes within the body responsible for maintaining homeostasis by providing the means to convert substrates to products as and when required. Physiological enzymes are tightly controlled by many signaling pathways and their products subsequently control other pathways. Traditionally, most drug discovery efforts focus on identifying enzyme inhibitors, due to upregulation being prevalent in many diseases and the existence of endogenous substrates that can be modified to afford inhibitor compounds. As enzyme downregulation and reduction of endogenous activators are observed in multiple diseases, the identification of small molecules with the ability to activate enzymes has recently entered the medicinal chemistry toolbox to afford chemical probes and potential therapeutics as an alternative means to intervene in diseases. In this review we highlight the progress made in the identification and advancement of non-kinase enzyme activators and their potential in treating various disease states.
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Affiliation(s)
- Louise F Dow
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center Omaha NE 68106 USA
| | - Alfie M Case
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center Omaha NE 68106 USA
| | - Megan P Paustian
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center Omaha NE 68106 USA
| | - Braeden R Pinkerton
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center Omaha NE 68106 USA
| | - Princess Simeon
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center Omaha NE 68106 USA
| | - Paul C Trippier
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center Omaha NE 68106 USA
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center Omaha NE 68106 USA
- UNMC Center for Drug Discovery, University of Nebraska Medical Center Omaha NE 68106 USA
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17
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Yang JL, Lin WL, Tai SB, Ciou YS, Chung CL, Chen JJ, Liu PF, Lin MW, Chen CL. Suppression of TGFβ-Induced Interleukin-6 Secretion by Sinulariolide from Soft Corals through Attenuation of the p38-NF-kB Pathway in Carcinoma Cells. Int J Mol Sci 2023; 24:11656. [PMID: 37511415 PMCID: PMC10380600 DOI: 10.3390/ijms241411656] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 07/13/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023] Open
Abstract
Sinulariolide (SC-1) is a natural product extracted from the cultured-type soft coral Sinularia flexibilis and possesses anti-inflammation, anti-proliferative, and anti-migratory in several types of cancer cells. However, the molecular pathway behind its effects on inflammation remains poorly understood. Since inflammatory cytokines such as TGFβ, TNFα, IL-1, IL-6, and IL-8 activate transcription factors such as Smads, NF-κB, STAT3, Snail, Twist, and Zeb that drive the epithelial-to-mesenchymal transition (EMT), in this study, we focus on the investigation in effects of SC-1 on TGFβ-induced interleukin-6 (IL-6) releases in an in vitro cell culture model. We showed that both intracellular IL-6 expression and secretion were stimulated by TGFβ and associated with strong upregulation of IL-6 mRNA and increased transcription in A549 cells. SC-1 blocked TGFβ-induced secretion of IL-6 while showing no effect on the induction of fibronectin and plasminogen activator inhibitor-1 genes, indicating that SC-1 interferes with only a subset of TGFβ activities. In addition, SC-1 inhibits TGFβ-induced IL-6 by suppressing p38 MAPK signaling and subsequently inhibits NF-κB and its nuclear translocation without affecting the canonical Smad pathway and receptor turnover. Overall, these data suggest that p38 may involve in the inhibition of SC-1 in IL-6 release, thus illustrating an inhibitory effect for SC-1 in the suppression of inflammation, EMT phenotype, and tumorigenesis.
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Affiliation(s)
- Jenq-Lin Yang
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
| | - Weng-Ling Lin
- Department of Pathology, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan
| | - Shun-Ban Tai
- Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
- Division of Rheumatology, Immunology and Allergy, Department of Internal Medicine, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung 81342, Taiwan
| | - Yi-Siang Ciou
- Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
| | - Chih-Ling Chung
- Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
| | - Jih-Jung Chen
- Department of Pharmacy, School of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404332, Taiwan
| | - Pei-Feng Liu
- Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
| | - Ming-Wei Lin
- Department of Medical Research, E-Da Hospital/E-Da Cancer Hospital, Kaohsiung 82445, Taiwan
| | - Chun-Lin Chen
- Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
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18
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Zou L, Zhou Y, Yu X, Chen C, Xiao G. Angiotensin I-Converting Enzyme Inhibitory Activity of Two Peptides Derived from In Vitro Digestion Products of Pork Sausage with Partial Substitution of NaCl by KCl. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023. [PMID: 37406188 DOI: 10.1021/acs.jafc.3c01149] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/07/2023]
Abstract
This study aimed to identify angiotensin I-converting enzyme (ACE) from in vitro digestion products of pork sausage with partial substitution of NaCl by KCl (PSRK). Peptides from in vitro digestion products of PSRK were identified through liquid chromatography with tandem mass spectrometry analysis coupled with de novo sequencing. Subsequently, the ACE inhibitory peptides LIVGFPAYGH and IVGFPAYGH were screened based on PeptideRanker, in silico absorption, molecular docking, and the determination of ACE inhibitory activity. In addition, the ACE inhibitory peptides LIVGFPAYGH and IVGFPAYGH were mixed-type inhibitors; these peptides' ACE inhibitory activities were expressed as the 50% inhibitory concentration (IC50) values in vitro, which were 196.16 and 150.88 μM, respectively. After 2 h of incubation, LIVGFPAYGH and IVGFPAYGH could be transported through Caco-2 cell monolayers with paracellular passive diffusion. Furthermore, LIVGFPAYGH and IVGFPAYGH significantly increased the levels of ACE2 and nitric oxide while decreasing the levels of ACE, angiotensin II, and endothelin-1 in Ang I-treated human umbilical vein endothelial cells, indicating the ACE inhibitory effect of LIVGFPAYGH and IVGFPAYGH. In summary, LIVGFPAYGH and IVGFPAYGH from PSRK can be used as functional foods with antihypertensive activity.
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Affiliation(s)
- Lifang Zou
- China Light Industry Key Laboratory of Meat Microbial Control and Utilization, Hefei University of Technology, Hefei 230009 Anhui Province, People's Republic of China
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009 Anhui Province, People's Republic of China
| | - Yu Zhou
- China Light Industry Key Laboratory of Meat Microbial Control and Utilization, Hefei University of Technology, Hefei 230009 Anhui Province, People's Republic of China
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009 Anhui Province, People's Republic of China
| | - Xia Yu
- China Light Industry Key Laboratory of Meat Microbial Control and Utilization, Hefei University of Technology, Hefei 230009 Anhui Province, People's Republic of China
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009 Anhui Province, People's Republic of China
| | - Conggui Chen
- China Light Industry Key Laboratory of Meat Microbial Control and Utilization, Hefei University of Technology, Hefei 230009 Anhui Province, People's Republic of China
- Engineering Research Center of Bio-process from Ministry of Education, Hefei University of Technology, Hefei 230009 Anhui Province, People's Republic of China
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009 Anhui Province, People's Republic of China
| | - Guiran Xiao
- China Light Industry Key Laboratory of Meat Microbial Control and Utilization, Hefei University of Technology, Hefei 230009 Anhui Province, People's Republic of China
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009 Anhui Province, People's Republic of China
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19
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Mia MS, Hossain D, Woodbury E, Kelleher S, Palamuttam RJ, Rao R, Steen P, Jarajapu YP, Mathew S. Integrin β1 is a key determinant of the expression of angiotensin-converting enzyme 2 (ACE2) in the kidney epithelial cells. Eur J Cell Biol 2023; 102:151316. [PMID: 37084657 PMCID: PMC11086052 DOI: 10.1016/j.ejcb.2023.151316] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 04/16/2023] [Accepted: 04/17/2023] [Indexed: 04/23/2023] Open
Abstract
The expression of the angiotensin-converting enzyme 2 (ACE2) is altered in multiple chronic kidney diseases like hypertension and renal fibrosis, where the signaling from the basal membrane proteins is critical for the development and progression of the various pathologies. Integrins are heterodimeric cell surface receptors that have important roles in the progression of these chronic kidney diseases by altering various cell signaling pathways in response to changes in the basement membrane proteins. It is unclear whether integrin or integrin-mediated signaling affects the ACE2 expression in the kidney. The current study tests the hypothesis that integrin β1 regulates the expression of ACE2 in kidney epithelial cells. The role of integrin β1 in ACE2 expression in renal epithelial cells was investigated by shRNA-mediated knockdown and pharmacological inhibition. In vivo studies were carried out using epithelial cell-specific deletion of integrin β1 in the kidneys. Deletion of integrin β1 from the mouse renal epithelial cells reduced the expression of ACE2 in the kidney. Furthermore, the downregulation of integrin β1 using shRNA decreased ACE2 expression in human renal epithelial cells. ACE2 expression levels were also decreased in renal epithelial cells and cancer cells when treated with an integrin α2β1 antagonist, BTT 3033. SARS-CoV-2 viral entry to human renal epithelial cells and cancer cells was also inhibited by BTT 3033. This study demonstrates that integrin β1 positively regulates the expression of ACE2, which is required for the entry of SARS-CoV-2 into kidney cells.
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Affiliation(s)
- Md Saimon Mia
- Department of Pharmaceutical Sciences, School of Pharmacy, North Dakota State University, Fargo, ND, USA
| | - Delowar Hossain
- Department of Pharmaceutical Sciences, School of Pharmacy, North Dakota State University, Fargo, ND, USA
| | - Emerson Woodbury
- Department of Pharmaceutical Sciences, School of Pharmacy, North Dakota State University, Fargo, ND, USA
| | - Sean Kelleher
- Department of Pharmaceutical Sciences, School of Pharmacy, North Dakota State University, Fargo, ND, USA
| | | | - Reena Rao
- Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA
| | - Preston Steen
- Sanford Health Roger Maris Cancer Center, Fargo, ND, USA
| | - Yagna Pr Jarajapu
- Department of Pharmaceutical Sciences, School of Pharmacy, North Dakota State University, Fargo, ND, USA
| | - Sijo Mathew
- Department of Pharmaceutical Sciences, School of Pharmacy, North Dakota State University, Fargo, ND, USA; Vanderbilt University Medical Center, Nashville, TN, USA.
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20
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Wang S, Wang Y, Deng Y, Zhang J, Jiang X, Yu J, Gan J, Zeng W, Guo M. Sacubitril/valsartan: research progress of multi-channel therapy for cardiorenal syndrome. Front Pharmacol 2023; 14:1167260. [PMID: 37214467 PMCID: PMC10196136 DOI: 10.3389/fphar.2023.1167260] [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: 02/16/2023] [Accepted: 04/17/2023] [Indexed: 05/24/2023] Open
Abstract
Cardiorenal syndrome (CRS) results from complex interaction between heart and kidneys, inducing simultaneous acute or chronic dysfunction of these organs. Although its incidence rate is increasing with higher mortality in patients, effective clinical treatment drugs are currently not available. The literature suggests that renin-angiotensin-aldosterone system (RAAS) and diuretic natriuretic peptide (NP) system run through CRS. Drugs only targeting the RAAS and NPs systems are not effective. Sacubitril/valsartan contains two agents (sacubitril and valsartan) that can regulate RAAS and NPs simultaneously. In the 2017 American College of Cardiology/American Heart Association/American Heart Failure (HF) ssociation (ACC/AHA/HFSA) guideline, sacubitril/valsartan was recommended as standard therapy for HF patients. The latest research shows that Combined levosimendan and Sacubitril/Valsartan markets are protected the heart and kidney against cardiovascular syndrome in rat. However, fewer studies have reported its therapeutic efficacy in CRS treatment, and their results are inconclusive. Therefore, based on RAAS and NPs as CRS biomarkers, this paper summarizes possible pathophysiological mechanisms and preliminary clinical application effects of sacubitril/valsartan in the prevention and treatment of CRS. This will provide a pharmacological justification for expanding sacubitril/valsartan use to the treatment of CRS.
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Affiliation(s)
- Shuangcui Wang
- Oncology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yuli Wang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yun Deng
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jiaqi Zhang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xijuan Jiang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jianchun Yu
- Oncology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jiali Gan
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Wenyun Zeng
- Traditional Chinese Medicine Department, Ganzhou People’s Hospital, Ganzhou, China
| | - Maojuan Guo
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
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21
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Kim K, Moon JH, Ahn CH, Lim S. Effect of olmesartan and amlodipine on serum angiotensin-(1-7) levels and kidney and vascular function in patients with type 2 diabetes and hypertension. Diabetol Metab Syndr 2023; 15:43. [PMID: 36899369 PMCID: PMC10005920 DOI: 10.1186/s13098-023-00987-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 01/27/2023] [Indexed: 03/12/2023] Open
Abstract
BACKGROUND Recent studies suggest that angiotensin-converting enzyme 2 (ACE2) and angiotensin-(1-7) [Ang-(1-7)] might have beneficial effects on the cardiovascular system. We investigated the effects of olmesartan on the changes in serum ACE2 and Ang-(1-7) levels as well as kidney and vascular function in patients with type 2 diabetes and hypertension. METHODS This was a prospective, randomized, active comparator-controlled trial. Eighty participants with type 2 diabetes and hypertension were randomized to receive 20 mg of olmesartan (N = 40) or 5 mg of amlodipine (N = 40) once daily. The primary endpoint was changes of serum Ang-(1-7) from baseline to week 24. RESULTS Both olmesartan and amlodipine treatment for 24 weeks decreased systolic and diastolic blood pressures significantly by > 18 mmHg and > 8 mmHg, respectively. Serum Ang-(1-7) levels were more significantly increased by olmesartan treatment (25.8 ± 34.5 pg/mL → 46.2 ± 59.4 pg/mL) than by amlodipine treatment (29.2 ± 38.9 pg/mL → 31.7 ± 26.0 pg/mL), resulting in significant between-group differences (P = 0.01). Serum ACE2 levels showed a similar pattern (6.31 ± 0.42 ng/mL → 6.74 ± 0.39 ng/mL by olmesartan treatment vs. 6.43 ± 0.23 ng/mL → 6.61 ± 0.42 ng/mL by amlodipine treatment; P < 0.05). The reduction in albuminuria was significantly associated with the increases in ACE2 and Ang-(1-7) levels (r = - 0.252 and r = - 0.299, respectively). The change in Ang-(1-7) levels was positively associated with improved microvascular function (r = 0.241, P < 0.05). Multivariate regression analyses showed that increases in serum Ang-(1-7) levels were an independent predictor of a reduction in albuminuria. CONCLUSIONS These findings suggest that the beneficial effects of olmesartan on albuminuria may be mediated by increased ACE2 and Ang-(1-7) levels. These novel biomarkers may be therapeutic targets for the prevention and treatment of diabetic kidney disease. TRIAL REGISTRATION ClinicalTrials.gov NCT05189015.
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Affiliation(s)
- Kyuho Kim
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea
- Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam, 463-707, South Korea
| | - Ji Hye Moon
- Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam, 463-707, South Korea
| | - Chang Ho Ahn
- Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam, 463-707, South Korea
| | - Soo Lim
- Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam, 463-707, South Korea.
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22
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Antiviral Molecular Targets of Essential Oils against SARS-CoV-2: A Systematic Review. Sci Pharm 2023. [DOI: 10.3390/scipharm91010015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/09/2023] Open
Abstract
Essential oils are potential therapeutics for coronavirus disease 2019 (COVID-19), in which some of the volatile compounds of essential oils have been well known for their broad antiviral activities. These therapeutic candidates have been shown to regulate the excessive secretion of pro-inflammatory cytokines, which underlies the pathogenesis of severe COVID-19. We aimed to identify molecular targets of essential oils in disrupting the cell entry and replication of SARS-CoV-2, hence being active as antivirals. Literature searches were performed on PubMed, Scopus, Scillit, and CaPlus/SciFinder (7 December 2022) with a truncated title implying the anti-SARS-CoV-2 activity of essential oil. Data were collected from the eligible studies and described narratively. Quality appraisal was performed on the included studies. A total of eight studies were included in this review; four of which used enzyme inhibition assay, one—pseudo-SARS-CoV-2 culture; two—whole SARS-CoV-2 culture; and one—ACE2-expressing cancer cells. Essential oils may prevent the SARS-CoV-2 infection by targeting its receptors on the cells (ACE2 and TMPRSS2). Menthol, 1,8-cineole, and camphor are among the volatile compounds which serve as potential ACE2 blockers. β-caryophyllene may selectively target the SARS-CoV-2 spike protein and inhibit viral entry. Other interactions with SARS-CoV-2 proteases and RdRp are observed based on molecular docking. In conclusion, essential oils could target proteins related to the SARS-CoV-2 entry and replication. Further studies with improved and uniform study designs should be carried out to optimize essential oils as COVID-19 therapies.
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23
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Gu G, Zhu B, Ren J, Song X, Fan B, Ding H, Shang J, Wu H, Li J, Wang H, Li J, Wei Z, Feng S. Ang-(1-7)/MasR axis promotes functional recovery after spinal cord injury by regulating microglia/macrophage polarization. Cell Biosci 2023; 13:23. [PMID: 36739421 PMCID: PMC9899400 DOI: 10.1186/s13578-023-00967-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 01/19/2023] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Inflammatory response is an essential part of secondary injury after spinal cord injury (SCI). During this period, the injury may be exacerbated through the release of a large number of inflammatory factors and the polarization of infiltrating macrophages and microglia towards M1. Ang-(1-7), mainly generated by Ang II via angiotensin-converting enzyme 2 (ACE2), can specifically bind to the G protein-coupled receptor Mas (MasR) and plays an important role in regulating inflammation and alleviating oxidative stress. METHODS We aimed to investigate whether activating the Ang-(1-7)/MasR axis in rats after SCI can regulate local neuroinflammation to achieve functional recovery and obtain its potential mechanism. MasR expression of bone marrow-derived macrophages was determined by Western blot. Immunofluorescence, Western blot, Flow cytometry, and RT-qPCR were applied to evaluate the polarization of Ang-(1-7) on macrophages and the regulation of inflammatory cytokines. Previous evaluation of the spinal cord and bladder after SCI was conducted by hematoxylin-eosin staining, Basso, Beattie, and Bresnahan (BBB) score, inclined plate test, electrophysiology, and catwalk were used to evaluate the functional recovery of rats. RESULTS MasR expression increased in macrophages under inflammatory conditions and further elevated after Ang-(1-7) treatment. Both in vivo and in vitro results confirmed that Ang-(1-7) could regulate the expression of inflammatory cytokines by down-regulating proinflammatory cytokines and up-regulating anti-inflammatory cytokines, and bias the polarization direction of microglia/macrophages to M2 phenotypic. After SCI, Ang-(1-7) administration in situ led to better histological and functional recovery in rats, and this recovery at least partly involved the TLR4/NF-κB signaling pathway. CONCLUSION As shown in our data, activating Ang-(1-7)/MasR axis can effectively improve the inflammatory microenvironment after spinal cord injury, promote the polarization of microglia/macrophages towards the M2 phenotype, and finally support the recovery of motor function. Therefore, we suggest using Ang-(1-7) as a feasible treatment strategy for spinal cord injury to minimize the negative consequences of the inflammatory microenvironment after spinal cord injury.
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Affiliation(s)
- Guangjin Gu
- grid.412645.00000 0004 1757 9434Tianjin Key Laboratory of Spine and Spinal Cord Injury, Department of Orthopedics, National Spinal Cord Injury International Cooperation Base, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin, 300052 China
| | - Bin Zhu
- grid.412645.00000 0004 1757 9434Tianjin Key Laboratory of Spine and Spinal Cord Injury, Department of Orthopedics, National Spinal Cord Injury International Cooperation Base, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin, 300052 China
| | - Jie Ren
- grid.412645.00000 0004 1757 9434Tianjin Key Laboratory of Spine and Spinal Cord Injury, Department of Orthopedics, National Spinal Cord Injury International Cooperation Base, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin, 300052 China
| | - Xiaomeng Song
- grid.412645.00000 0004 1757 9434Tianjin Key Laboratory of Spine and Spinal Cord Injury, Department of Orthopedics, National Spinal Cord Injury International Cooperation Base, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin, 300052 China
| | - Baoyou Fan
- grid.412645.00000 0004 1757 9434Tianjin Key Laboratory of Spine and Spinal Cord Injury, Department of Orthopedics, National Spinal Cord Injury International Cooperation Base, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin, 300052 China
| | - Han Ding
- grid.412645.00000 0004 1757 9434Tianjin Key Laboratory of Spine and Spinal Cord Injury, Department of Orthopedics, National Spinal Cord Injury International Cooperation Base, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin, 300052 China
| | - Jun Shang
- grid.412645.00000 0004 1757 9434Tianjin Key Laboratory of Spine and Spinal Cord Injury, Department of Orthopedics, National Spinal Cord Injury International Cooperation Base, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin, 300052 China
| | - Heng Wu
- grid.412645.00000 0004 1757 9434Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Junjin Li
- grid.412645.00000 0004 1757 9434Tianjin Key Laboratory of Spine and Spinal Cord Injury, Department of Orthopedics, National Spinal Cord Injury International Cooperation Base, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin, 300052 China
| | - Hongda Wang
- grid.412645.00000 0004 1757 9434Tianjin Key Laboratory of Spine and Spinal Cord Injury, Department of Orthopedics, National Spinal Cord Injury International Cooperation Base, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin, 300052 China
| | - Jinze Li
- grid.412645.00000 0004 1757 9434Tianjin Key Laboratory of Spine and Spinal Cord Injury, Department of Orthopedics, National Spinal Cord Injury International Cooperation Base, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin, 300052 China
| | - Zhijian Wei
- grid.412645.00000 0004 1757 9434Tianjin Key Laboratory of Spine and Spinal Cord Injury, Department of Orthopedics, National Spinal Cord Injury International Cooperation Base, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin, 300052 China ,Department of Orthopaedics, Qilu Hospital of Shandong University, Shandong University Centre for Orthopaedics, Advanced Medical Research Institute, Shandong University, Jinan, Shandong China
| | - Shiqing Feng
- grid.412645.00000 0004 1757 9434Tianjin Key Laboratory of Spine and Spinal Cord Injury, Department of Orthopedics, National Spinal Cord Injury International Cooperation Base, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin, 300052 China ,Department of Orthopaedics, Qilu Hospital of Shandong University, Shandong University Centre for Orthopaedics, Advanced Medical Research Institute, Shandong University, Jinan, Shandong China
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24
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Bertaud A, Joshkon A, Heim X, Bachelier R, Bardin N, Leroyer AS, Blot-Chabaud M. Signaling Pathways and Potential Therapeutic Strategies in Cardiac Fibrosis. Int J Mol Sci 2023; 24:ijms24021756. [PMID: 36675283 PMCID: PMC9866199 DOI: 10.3390/ijms24021756] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/06/2023] [Accepted: 01/11/2023] [Indexed: 01/17/2023] Open
Abstract
Cardiac fibrosis constitutes irreversible necrosis of the heart muscle as a consequence of different acute (myocardial infarction) or chronic (diabetes, hypertension, …) diseases but also due to genetic alterations or aging. Currently, there is no curative treatment that is able to prevent or attenuate this phenomenon that leads to progressive cardiac dysfunction and life-threatening outcomes. This review summarizes the different targets identified and the new strategies proposed to fight cardiac fibrosis. Future directions, including the use of exosomes or nanoparticles, will also be discussed.
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25
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Chen XS, Cui JR, Meng XL, Wang SH, Wei W, Gao YL, Shou ST, Liu YC, Chai YF. Angiotensin-(1-7) ameliorates sepsis-induced cardiomyopathy by alleviating inflammatory response and mitochondrial damage through the NF-κB and MAPK pathways. J Transl Med 2023; 21:2. [PMID: 36593471 PMCID: PMC9807106 DOI: 10.1186/s12967-022-03842-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 12/20/2022] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND There is no available viable treatment for Sepsis-Induced Cardiomyopathy (SIC), a common sepsis complication with a higher fatality risk. The septic patients showed an abnormal activation of the renin angiotensin (Ang) aldosterone system (RAAS). However, it is not known how the Ang II and Ang-(1-7) affect SIC. METHODS Peripheral plasma was collected from the Healthy Control (HC) and septic patients and Ang II and Ang-(1-7) protein concentrations were measured. The in vitro and in vivo models of SIC were developed using Lipopolysaccharide (LPS) to preliminarily explore the relationship between the SIC state, Ang II, and Ang-(1-7) levels, along with the protective function of exogenous Ang-(1-7) on SIC. RESULTS Peripheral plasma Ang II and the Ang II/Ang-(1-7) levels in SIC-affected patients were elevated compared to the levels in HC and non-SIC patients, however, the HC showed higher Ang-(1-7) levels. Furthermore, peripheral plasma Ang II, Ang II/Ang-(1-7), and Ang-(1-7) levels in SIC patients were significantly correlated with the degree of myocardial injury. Additionally, exogenous Ang-(1-7) can attenuate inflammatory response, reduce oxidative stress, maintain mitochondrial dynamics homeostasis, and alleviate mitochondrial structural and functional damage by inhibiting nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, thus alleviating SIC. CONCLUSIONS Plasma Ang-(1-7), Ang II, and Ang II/Ang-(1-7) levels were regarded as significant SIC biomarkers. In SIC, therapeutic targeting of RAAS, for example with Ang-(1-7), may exert protective roles against myocardial damage.
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Affiliation(s)
- Xin-Sen Chen
- grid.412645.00000 0004 1757 9434Department of Emergency Medicine, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin, 300052 China
| | - Jing-Rui Cui
- grid.412645.00000 0004 1757 9434Department of Emergency Medicine, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin, 300052 China
| | - Xiang-Long Meng
- grid.412645.00000 0004 1757 9434Department of Emergency Medicine, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin, 300052 China
| | - Shu-Hang Wang
- grid.412645.00000 0004 1757 9434Department of Emergency Medicine, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin, 300052 China
| | - Wei Wei
- grid.412645.00000 0004 1757 9434Department of Emergency Medicine, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin, 300052 China
| | - Yu-Lei Gao
- grid.412645.00000 0004 1757 9434Department of Emergency Medicine, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin, 300052 China
| | - Song-Tao Shou
- grid.412645.00000 0004 1757 9434Department of Emergency Medicine, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin, 300052 China
| | - Yan-Cun Liu
- grid.412645.00000 0004 1757 9434Department of Emergency Medicine, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin, 300052 China
| | - Yan-Fen Chai
- grid.412645.00000 0004 1757 9434Department of Emergency Medicine, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin, 300052 China
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Dos Anjos AA, de Paiva IT, Simões Lima GL, da Silva Filha R, Fróes BPE, Brant Pinheiro SV, Silva ACSE. Nephrotic Syndrome and Renin-angiotensin System: Pathophysiological Role and Therapeutic Potential. Curr Mol Pharmacol 2023; 16:465-474. [PMID: 35713131 DOI: 10.2174/1874467215666220616152312] [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: 02/02/2022] [Revised: 05/14/2022] [Accepted: 05/19/2022] [Indexed: 11/22/2022]
Abstract
Idiopathic Nephrotic Syndrome (INS) is the most frequent etiology of glomerulopathy in pediatric patients and one of the most common causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in this population. In this review, we aimed to summarize evidence on the pathophysiological role and therapeutic potential of the Renin-Angiotensin System (RAS) molecules for the control of proteinuria and for delaying the onset of CKD in patients with INS. This is a narrative review in which the databases PubMed, Web of Science, and Sci- ELO were searched for articles about INS and RAS. We selected articles that evaluated the pathophysiological role of RAS and the effects of the alternative RAS axis as a potential therapy for INS. Several studies using rodent models of nephropathies showed that the treatment with activators of the Angiotensin-Converting Enzyme 2 (ACE2) and with Mas receptor agonists reduces proteinuria and improves kidney tissue damage. Another recent paper showed that the reduction of urinary ACE2 levels in children with INS correlates with proteinuria and higher concentrations of inflammatory cytokines, although data with pediatric patients are still limited. The molecules of the alternative RAS axis comprise a wide spectrum, not yet fully explored, of potential pharmacological targets for kidney diseases. The effects of ACE2 activators and receptor Mas agonists show promising results that can be useful for nephropathies including INS.
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Affiliation(s)
- Alessandra Aguiar Dos Anjos
- Departamento de Pediatria, Faculdade de Medicina, Unidade de Nefrologia Pediátrica, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil
| | - Isadora Tucci de Paiva
- Departamento de Pediatria, Faculdade de Medicina, Unidade de Nefrologia Pediátrica, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil
| | - Giovanna Letícia Simões Lima
- Faculdade de Medicina, Laboratório Interdisciplinar de Investigação Médica, UFMG, Belo Horizonte, Minas Gerais, Brazil
| | - Roberta da Silva Filha
- Faculdade de Medicina, Laboratório Interdisciplinar de Investigação Médica, UFMG, Belo Horizonte, Minas Gerais, Brazil
| | - Brunna Pinto E Fróes
- Departamento de Pediatria, Faculdade de Medicina, Unidade de Nefrologia Pediátrica, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil
| | - Sérgio Veloso Brant Pinheiro
- Departamento de Pediatria, Faculdade de Medicina, Unidade de Nefrologia Pediátrica, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil
| | - Ana Cristina Simões E Silva
- Departamento de Pediatria, Faculdade de Medicina, Unidade de Nefrologia Pediátrica, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil
- Faculdade de Medicina, Laboratório Interdisciplinar de Investigação Médica, UFMG, Belo Horizonte, Minas Gerais, Brazil
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27
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Feng L, Fu S, Zhang P, Zhang Y, Zhao Y, Yao Y, Luo L, Ping P. Potential use of the S-protein-Angiotensin converting enzyme 2 binding pathway in the treatment of coronavirus disease 2019. Front Public Health 2022; 10:1050034. [PMID: 36518573 PMCID: PMC9742547 DOI: 10.3389/fpubh.2022.1050034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 11/15/2022] [Indexed: 11/29/2022] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen that causes coronavirus disease 2019 (COVID-19), infects humans through a strong interaction between the viral spike protein (S-protein) and angiotensin converting enzyme 2 (ACE2) receptors on the cell surface. The infection of host lung cells by SARS-CoV-2 leads to clinical symptoms in patients. However, ACE2 expression is not restricted to the lungs; altered receptors have been found in the nasal and oral mucosa, vessel, brain, pancreas, gastrointestinal tract, kidney, and heart. The future of COVID-19 is uncertain, however, new viral variants are likely to emerge. The SARS-CoV-2 Omicron variant has a total of 50 gene mutations compared with the original virus; 15 of which occur in the receptor binding domain (RBD). The RBD of the viral S-protein binds to the human ACE2 receptor for viral entry. Mutations of the ACE2-RBD interface enhance tight binding by increasing hydrogen bond interactions and expanding the accessible surface area. Extracorporeal membrane oxygenation, hyperbaric oxygen, and aggressive dialysis for the treatment of COVID-19 have shown various degrees of clinical success. The use of decoy receptors based on the ACE2 receptor as a broadly potent neutralizer of SARS-CoV-2 variants has potential as a therapeutic mechanism. Drugs such as 3E8 could block binding of the S1-subunit to ACE2 and restrict the infection of ACE2-expressing cells by a variety of coronaviruses. Here, we discuss the development of ACE2-targeted strategies for the treatment and prevention of COVID-19.
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Affiliation(s)
- Long Feng
- Department of Anesthesia, Hainan Hospital of Chinese People's Liberation Army General Hospital, Sanya, China
| | - Shihui Fu
- Department of Geriatric Cardiology, Chinese People's Liberation Army General Hospital, Beijing, China
- Department of Cardiology, Hainan Hospital of Chinese People's Liberation Army General Hospital, Sanya, China
| | - Pei Zhang
- School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Yujie Zhang
- Department of Epidemiology, School of Public Health, Southern Medical University, Guangzhou, China
| | - Yali Zhao
- Central Laboratory, Hainan Hospital of Chinese People's Liberation Army General Hospital, Sanya, China
| | - Yao Yao
- Center for Healthy Aging and Development Studies, National School of Development, Peking University, Beijing, China
| | - Leiming Luo
- Department of Geriatric Cardiology, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Ping Ping
- General Station for Drug and Instrument Supervision and Control, Joint Logistic Support Force of Chinese People's Liberation Army, Beijing, China
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Miura Y, Ohkubo H, Nakano A, Bourke JE, Kanazawa S. Pathophysiological conditions induced by SARS-CoV-2 infection reduce ACE2 expression in the lung. Front Immunol 2022; 13:1028613. [PMID: 36405683 PMCID: PMC9673245 DOI: 10.3389/fimmu.2022.1028613] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 10/14/2022] [Indexed: 04/03/2024] Open
Abstract
SARS-CoV-2 infection causes a variety of physiological responses in the lung, and understanding how the expression of SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), and its proteolytic activator, transmembrane serine protease 2 (TMPRSS2), are affected in patients with underlying disease such as interstitial pneumonia will be important in considering COVID-19 progression. We examined the expression of ACE2 and TMPRSS2 in an induced usual interstitial pneumonia (iUIP) mouse model and patients with IPF as well as the changes in whole-lung ACE2 and TMPRSS2 expression under physiological conditions caused by viral infection. Histopathological and biochemical characteristics were analyzed using human specimens from patients with IPF and precision-cut lung slices (PCLS) from iUIP mouse model showing UIP with honeycombing and severe fibrosis after non-specific interstitial pneumonia. ACE2 expression decreased with acute lung inflammation and increased in the abnormal lung epithelium of the iUIP mouse model. ACE2 is also expressed in metaplastic epithelial cells. Poly(I:C), interferons, and cytokines associated with fibrosis decreased ACE2 expression in PCLS in the iUIP model. Hypoxia also decreases ACE2 via HIF1α in PCLS. Antifibrotic agent, nintedanib attenuates ACE2 expression in invasive epithelial cells. Patients with IPF are at a higher risk of SARS-CoV-2 infection due to the high expression of ACE2. However, ACE2 and TMPRSS2 expression is decreased by immune intermediaries, including interferons and cytokines that are associated with viral infection and upon administration of antifibrotic agents, suggesting that most of the viral infection-induced pathophysiological responses aid the development of resistance against SARS-CoV-2 infection.
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Affiliation(s)
- Yoko Miura
- Department of Neurodevelopmental Disorder Genetics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Hirotsugu Ohkubo
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Akiko Nakano
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Jane E. Bourke
- Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, VA, Australia
| | - Satoshi Kanazawa
- Department of Neurodevelopmental Disorder Genetics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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Guo Y, Guo K, Hu T, Wu D. Correlation between serum angiotensin-converting enzyme (ACE) levels and intervertebral disc degeneration. Peptides 2022; 157:170867. [PMID: 36055434 DOI: 10.1016/j.peptides.2022.170867] [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: 05/17/2022] [Revised: 08/12/2022] [Accepted: 08/28/2022] [Indexed: 10/31/2022]
Abstract
Studies have shown that the renin-angiotensin system (RAS) might play an essential role in intervertebral disc degeneration (IDD). The study aimed to investigate the relationship between serum angiotensin-converting enzyme (ACE) concentration and IDD and its predictive value for severe disc degeneration. 245 patients who came to our hospital for low back pain were recruited, and blood samples were collected for routine examination. Descriptive data and demographic parameters were collected. The cumulative grade 1 was calculated by summing up the Pfirrmann grade of all lumbar discs. ACE concentration grouping was determined via tertile split. Correlation analysis and multivariable linear regression analysis were performed to determine the relationship between ACE and IDD. The receiver's degree of disc degeneration (ROC) curve determined the ACE's predictive value. Results indicated that there was no significant difference in demographic parameters among groups. Correlation analysis and multivariate linear analysis showed that ACE was an independent risk factor for IDD. The cumulative grade 1 increased significantly with the increase in ACE concentration, which was consistent with the correlation analysis. Average Pfirrmann grade < 4 indicates mild to moderate degeneration, and grade ≥ 4 indicates severe degeneration in terms of an individual disc. From L1/2 to L5/S1, the mean plasma ACE concentration was significantly higher in the severe degeneration group than in the mild to moderate degeneration group. According to the ROC curve, the cut-off value of ACE levels was 22.5. patients with ACE > 22.5 had severe degeneration. The sensitivity and specificity were 0.762 and 0.521, respectively.
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Affiliation(s)
- Youfeng Guo
- Department of Spine Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Kai Guo
- Department of Spine Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Tao Hu
- Department of Spine Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
| | - Desheng Wu
- Department of Spine Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
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Identification and characterization of a novel tetrapeptide from enzymatic hydrolysates of Baijiu byproduct. FOOD SCIENCE AND HUMAN WELLNESS 2022. [DOI: 10.1016/j.fshw.2022.06.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Abstract
Background Musculoskeletal involvement was the least addressed area of post covid 19 infection sequela in literature even though they significantly reflect in mobility of survivors and ends up in morbidity. Emphasis on this grey area may enlighten further researches on the same.The study aims to identify the relationship between Covid 19 infection and avascular necrosis of femoral head, by retrospectively assessing the COVID 19 history of patients who attended a tertiary center. Materials and methods Study Period: 26/7/2021 – 26/7/2022).The data of all the patients diagnosed with avascular necrosis of hip during from 26/7/21 to 26/7/22were retrospectively assessed to identify the history of COVID 19. Results A total of 17 patients were available for the study,the mean age of the patients were 37 years (range 23-60). Out of the 17 patients 7 were female and 10 were male. All the patients were presented to the OPD with hip pain.On assessing the history of COVID 19 it was found that out of the total 17 patients, 14 had history of COVID 19 infection (82.4%).On detailed history assessment, it was also found that all the 14 post Covid patients had their symptoms onset after COVID.The retrospective analysis of the AVN patients over the study period of one year indicates that the 82.4% of the patients had history of COVID prior to the onset of AVN symptoms, with average duration of onset of symptoms post COVID being 66 days. Conclusion Early diagnosis of post Covid 19 infection AVN hip can direct the management spectrum to its lower extremities and need of a case control study to confirm the causative effect Covid19 infection on avascular necrosis of hip were suggested.
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Cheng J, Xue F, Cheng C, Sui W, Zhang M, Qiao L, Ma J, Ji X, Chen W, Yu X, Xi B, Xu F, Su G, Zhao Y, Hao P, Zhang Y, Zhang C. ADAM17 knockdown mitigates while ADAM17 overexpression aggravates cardiac fibrosis and dysfunction via regulating ACE2 shedding and myofibroblast transformation. Front Pharmacol 2022; 13:997916. [PMID: 36313337 PMCID: PMC9613967 DOI: 10.3389/fphar.2022.997916] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 10/03/2022] [Indexed: 11/13/2022] Open
Abstract
A disintegrin and metalloprotease domain family protein 17 (ADAM17) is a new member of renin-angiotensin system (RAS) but its role in the pathogenesis of diabetic cardiomyopathy (DCM) is obscure. To test the hypothesis that ADAM17 knockdown mitigates while ADAM17 overexpression aggravates cardiac fibrosis via regulating ACE2 shedding and myofibroblast transformation in diabetic mice, ADAM17 gene was knocked down and overexpressed by means of adenovirus-mediated short-hairpin RNA (shRNA) and adenovirus vector carrying ADAM17 cDNA, respectively, in a mouse model of DCM. Two-dimensional and Doppler echocardiography, histopathology and immunohistochemistry were performed in all mice and in vitro experiments conducted in primary cardiofibroblasts. The results showed that ADAM17 knockdown ameliorated while ADAM17 overexpression worsened cardiac dysfunction and cardiac fibrosis in diabetic mice. In addition, ADAM17 knockdown increased ACE2 while reduced AT1R expression in diabetic hearts. Mechanistically, ADAM17 knockdown decreased while ADAM17 overexpression increased cardiac fibroblast-to-myofibroblast transformation through regulation of TGF-β1/Smad3 signaling pathway. In conclusion, ADAM17 knockdown attenuates while ADAM17 overexpression aggravates cardiac fibrosis via regulating ACE2 shedding and myofibroblast transformation through TGF-β1/Smad3 signaling pathway in diabetic mice. Targeting ADAM17 may provide a promising approach to the prevention and treatment of cardiac fibrosis in DCM.
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Affiliation(s)
- Jing Cheng
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Fei Xue
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Cheng Cheng
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Wenhai Sui
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Meng Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Lei Qiao
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jing Ma
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xiaoping Ji
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Wenqiang Chen
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xiao Yu
- Key Laboratory Experimental Teratology of the Ministry of Education, Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Bo Xi
- Department of Epidemiology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Feng Xu
- Department of Emergency Medicine, Chest Pain Center, Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Qilu Hospital, Shandong University, Jinan, China
| | - Guohai Su
- Cardiovascular Disease Research Center of Shandong First Medical University, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yuxia Zhao
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Traditional Chinese Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Panpan Hao
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yun Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Cardiovascular Disease Research Center of Shandong First Medical University, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Cheng Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Cardiovascular Disease Research Center of Shandong First Medical University, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
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Chen XS, Wang SH, Liu CY, Gao YL, Meng XL, Wei W, Shou ST, Liu YC, Chai YF. Losartan attenuates sepsis-induced cardiomyopathy by regulating macrophage polarization via TLR4-mediated NF-κB and MAPK signaling. Pharmacol Res 2022; 185:106473. [PMID: 36182039 DOI: 10.1016/j.phrs.2022.106473] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 09/25/2022] [Accepted: 09/25/2022] [Indexed: 11/17/2022]
Abstract
Sepsis-induced cardiomyopathy (SIC) is a serious complication of sepsis with high mortality but no effective treatment. The renin angiotensin (Ang) aldosterone system (RAAS) is activated in patients with sepsis but it is unclear how the Ang II/Ang II type 1 receptor (AT1R) axis contributes to SIC. This study examined the link between the Ang II/AT1R axis and SIC as well as the protective effect of AT1R blockers (ARBs). The Ang II level in peripheral plasma and AT1R expression on monocytes were significantly higher in patients with SIC compared with those in non-SIC patients and healthy controls and were correlated with the degree of myocardial injury. The ARB losartan reduced the infiltration of neutrophils, monocytes, and macrophages into the heart and spleen of SIC mice. Additionally, losartan regulated macrophage polarization from the M1 to the M2 subtype via nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, thereby maintaining the mitochondrial dynamics balance in cardiomyocytes and reducing oxidative stress and cardiomyocyte apoptosis. In conclusion, the plasma Ang II level and AT1R expression on plasma monocytes are an important biomarker in SIC. Therapeutic targeting of AT1R, for example with losartan, can potentially protect against myocardial injury in SIC.
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Affiliation(s)
- Xin-Sen Chen
- Department of Emergency Medicine, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin 300052, China
| | - Shu-Hang Wang
- Department of Emergency Medicine, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin 300052, China
| | - Chen-Yan Liu
- Department of Emergency Medicine, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin 300052, China
| | - Yu-Lei Gao
- Department of Emergency Medicine, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin 300052, China
| | - Xiang-Long Meng
- Department of Emergency Medicine, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin 300052, China
| | - Wei Wei
- Department of Emergency Medicine, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin 300052, China
| | - Song-Tao Shou
- Department of Emergency Medicine, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin 300052, China
| | - Yan-Cun Liu
- Department of Emergency Medicine, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin 300052, China.
| | - Yan-Fen Chai
- Department of Emergency Medicine, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin 300052, China.
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Zhao K, Xu T, Mao Y, Wu X, Hua D, Sheng Y, Li P. Alamandine alleviated heart failure and fibrosis in myocardial infarction mice. Biol Direct 2022; 17:25. [PMID: 36167556 PMCID: PMC9516792 DOI: 10.1186/s13062-022-00338-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 09/20/2022] [Indexed: 11/10/2022] Open
Abstract
Alamandine (Ala) is the newest identified peptide of the renin-angiotensin system and has protective effect on myocyte hypertrophy. However, it is still unclear whether Ala can alleviate heart failure (HF). The aim of this study was to explore the effects of Ala on HF and the related cardiac fibrosis, and to probe the mechanism. HF model was induced by myocardial infarction (MI) in mice. Four weeks after MI, Ala was administrated by intraperitoneal injection for two weeks. Ala injection significantly improved cardiac dysfunction of MI mice in vivo. The cardiac fibrosis and the related biomarkers were attenuated after Ala administration in HF mice in vivo. The increases of collagen I, alpha-smooth muscle actin and transforming growth factor-beta induced by oxygen–glucose deprivation (OGD) in neonatal rat cardiac fibroblasts (NRCFs) were inhibited by Ala treatment in vitro. The biomarkers of apoptosis were elevated in NRCFs induced by OGD, which were attenuated after treating with Ala in vitro. The enhancement of oxidative stress in the heart of MI mice or in the NRCFs treated with OGD was suppressed by treating with Ala in vivo and in vitro. These effects of Ala were reversed by tBHP, an exogenous inducer of oxidative stress in vitro. These results demonstrated that Ala could alleviate cardiac dysfunction and attenuate cardiac fibrosis via inhibition of oxidative stress.
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Affiliation(s)
- Kun Zhao
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Tianhua Xu
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Yukang Mao
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Xiaoguang Wu
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Dongxu Hua
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Yanhui Sheng
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China. .,Department of Cardiology, Jiangsu Province Hospital, Nanjing, Jiangsu, China.
| | - Peng Li
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China.
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Bošković M, Živković M, Koricanac G, Tepavcevic S, Zec M, Debeljak-Martacic J, Stanković A. Walnut supplementation after fructose-rich diet is associated with a beneficial fatty acid ratio and increased ACE2 expression in the rat heart. Front Physiol 2022; 13:942459. [PMID: 36213224 PMCID: PMC9533082 DOI: 10.3389/fphys.2022.942459] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 09/06/2022] [Indexed: 11/13/2022] Open
Abstract
Increased fructose consumption has been linked with chronic inflammation and metabolic syndrome (MetS). Activation of the renin-angiotensin system (RAS) and NF-κB have been detected in MetS. Walnuts are a rich source of polyunsaturated omega-3 fatty acids (n-3 PUFA) that were suggested to exert anti-inflammatory effects related to cardio-metabolic health. We hypothesized that walnut supplementation has the capacity to revert unfavorable fructose-rich diet (FRD)-induced activation of cardiac RAS and NF-κB in male rats. Due to the lack of similar studies, we investigated the effects of walnut supplementation (6 weeks) on the expression of four RAS molecules (ACE, ACE2, AT1R, and AT2R) and NF-κB in rat heart after FRD (10% w/v, 9 weeks). In addition, we followed the changes in the n-6/n-3 PUFA ratio in the total pool of heart lipids after both treatments to elucidate the walnut effects on fatty acids in the heart. 36 animals (9 per group) participated in the experiment. FRD significantly increased the ACE protein level in the heart (p < 0.001). Walnut supplementation significantly increased the ACE2 protein level in the heart of FRD (p < 0.001). In addition, walnut supplementation showed a significant main effect on the arachidonic acid/eicosapentaenoic acid ratio (p = 0.004). Walnut supplementation significantly reduced this ratio, in comparison with both, the control group (C vs. FW, p < 0.05) and the FRD group (F vs. FW, p < 0.05). However, walnut treatment failed to revert the significant effect of fructose (p < 0.001) on the elevation of NF-κB protein level. Our results suggest a beneficial effect of walnut supplementation on ACE2 protein level and n-6/n-3 PUFA level in the heart of the animal model of MetS. Such results highlight the approach of omega-3-rich walnut supplementation in the stimulation of endogenous production of favorable molecules in the heart which could be an affordable nutritional treatment formaintenance of cardio-metabolic health.
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Affiliation(s)
- Maja Bošković
- Laboratory for Radiobiology and Molecular Genetics, “VINČA” Institute of Nuclear Sciences—National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Maja Živković
- Laboratory for Radiobiology and Molecular Genetics, “VINČA” Institute of Nuclear Sciences—National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Goran Koricanac
- Laboratory for Molecular Biology and Endocrinology, “VINČA” Institute of Nuclear Sciences—National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Snezana Tepavcevic
- Laboratory for Molecular Biology and Endocrinology, “VINČA” Institute of Nuclear Sciences—National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Manja Zec
- School of Nutritional Sciences and Wellness, University of Arizona, Tucson, AZ, United States
| | - Jasmina Debeljak-Martacic
- Centre of Excellence in Nutrition and Metabolism Research, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Aleksandra Stanković
- Laboratory for Radiobiology and Molecular Genetics, “VINČA” Institute of Nuclear Sciences—National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
- *Correspondence: Aleksandra Stanković,
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Interactions between the intrarenal dopaminergic and the renin-angiotensin systems in the control of systemic arterial pressure. Clin Sci (Lond) 2022; 136:1205-1227. [PMID: 35979889 DOI: 10.1042/cs20220338] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 07/31/2022] [Accepted: 08/03/2022] [Indexed: 11/17/2022]
Abstract
Systemic arterial hypertension is one of the leading causes of morbidity and mortality in the general population, being a risk factor for many cardiovascular diseases. Although its pathogenesis is complex and still poorly understood, some systems appear to play major roles in its development. This review aims to update the current knowledge on the interaction of the intrarenal renin-angiotensin system (RAS) and dopaminergic system in the development of hypertension, focusing on recent scientific hallmarks in the field. The intrarenal RAS, composed of several peptides and receptors, has a critical role in the regulation of blood pressure (BP) and, consequently, the development of hypertension. The RAS is divided into two main intercommunicating axes: the classical axis, composed of angiotensin-converting enzyme, angiotensin II, and angiotensin type 1 receptor, and the ACE2/angiotensin-(1-7)/Mas axis, which appears to modulate the effects of the classical axis. Dopamine and its receptors are also increasingly showing an important role in the pathogenesis of hypertension, as abnormalities in the intrarenal dopaminergic system impair the regulation of renal sodium transport, regardless of the affected dopamine receptor subtype. There are five dopamine receptors, which are divided into two major subtypes: the D1-like (D1R and D5R) and D2-like (D2R, D3R, and D4R) receptors. Mice deficient in any of the five dopamine receptor subtypes have increased BP. Intrarenal RAS and the dopaminergic system have complex interactions. The balance between both systems is essential to regulate the BP homeostasis, as alterations in the control of both can lead to hypertension.
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Govender N, Khaliq O, Moodley J, Naicker T. Unravelling the Mechanistic Role of ACE2 and TMPRSS2 in Hypertension: A Risk Factor for COVID-19. Curr Hypertens Rev 2022; 18:130-137. [PMID: 36508271 DOI: 10.2174/1573402118666220816090809] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/25/2022] [Accepted: 05/30/2022] [Indexed: 01/27/2023]
Abstract
BACKGROUND This review explores the mechanistic action of angiotensin-converting enzyme- 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) in the renin-angiotensinaldosterone system (RAAS) that predisposes hypertensive patients to the adverse outcome of severe COVID-19. METHODS AND RESULTS Entry of SARS-CoV-2 into the host cell via ACE2 disrupts the RAAS system, creating an imbalance between ACE and ACE2, with an increased inflammatory response, leading to hypertension (HTN), pulmonary vasoconstriction and acute respiratory distress. SARSCoV- 2 may also predispose infected individuals with existing HTN to a greater risk of severe COVID-19 complications. In the duality of COVID-19 and HTN, the imbalance of ACE and ACE2 results in an elevation of AngII and a decrease in Ang (1-7), a hyperinflammatory response and endothelial dysfunction. Endothelial dysfunction is the main factor predisposing hypertensive patients to severe COVID-19 and vice-versa. CONCLUSION Despite the increase in ACE2 expression in hypertensive SARS-CoV-2 infected patients, ARBs/ACE inhibitors do not influence their severity and clinical outcomes, implicating continued usage. Future large-scale clinical trials are warranted to further elucidate the association between HTN and SARS-CoV-2 infection and the use of ARBs/ACEIs in SARS-CoV-2 hypertensive patients.
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Affiliation(s)
- Nalini Govender
- Department of Basic Medical Sciences, Faculty of Health Sciences, Durban University of Technology, Durban 4001, South Africa
| | - Olive Khaliq
- The Department of Paediatrics and Child Health, Faculty of Health Sciences, The University of the Free State, Bloemfontein 9300, South Africa
| | - Jagidesa Moodley
- Women's Health and HIV Research Group, Department of Obstetrics and Gynaecology, School of Clinical Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban 4001, South Africa
| | - Thajasvarie Naicker
- Optics & Imaging Centre, Doris Duke Medical Research Institute, College of Health Sciences, University of KwaZulu-Natal, Durban 4001, South Africa
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Chiorescu RM, Lazar RD, Buksa SB, Mocan M, Blendea D. Biomarkers of Volume Overload and Edema in Heart Failure With Reduced Ejection Fraction. Front Cardiovasc Med 2022; 9:910100. [PMID: 35783848 PMCID: PMC9247259 DOI: 10.3389/fcvm.2022.910100] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 05/23/2022] [Indexed: 12/19/2022] Open
Abstract
From a pathogenetic point of view, heart failure (HF) is characterized by the activation of several neurohumoral pathways with a role in maintaining the cardiac output and the adequate perfusion pressure in target organs and tissues. Decreased cardiac output in HF with reduced ejection fraction causes activation of the sympathetic nervous system, the renin angiotensin aldosterone system, arginine-vasopressin system, natriuretic peptides, and endothelin, all of which cause water and salt retention in the body. As a result, patients will present clinically as the main symptoms: dyspnea and peripheral edema caused by fluid redistribution to the lungs and/or by fluid overload. By studying these pathophysiological mechanisms, biomarkers with a prognostic and therapeutic role in the management of edema were identified in patients with HF with low ejection fraction. This review aims to summarize the current data from the specialty literature of such biomarkers with a role in the pathogenesis of edema in HF with low ejection fraction. These biomarkers may be the basis for risk stratification and the development of new therapeutic means in the treatment of edema in these patients.
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Affiliation(s)
- Roxana Mihaela Chiorescu
- Department of Internal Medicine, “Iuliu Haţieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Department of Internal Medicine, Emergency Clinical County Hospital, Cluj-Napoca, Romania
| | - Roxana-Daiana Lazar
- Nicolae Stancioiu Heart Institute, Cluj-Napoca, Romania
- *Correspondence: Roxana-Daiana Lazar
| | - Sándor-Botond Buksa
- Department of Internal Medicine, Emergency Clinical County Hospital, Cluj-Napoca, Romania
| | - Mihaela Mocan
- Department of Internal Medicine, “Iuliu Haţieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Department of Internal Medicine, Emergency Clinical County Hospital, Cluj-Napoca, Romania
| | - Dan Blendea
- Department of Internal Medicine, “Iuliu Haţieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Nicolae Stancioiu Heart Institute, Cluj-Napoca, Romania
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Zhu P, Zhang W, Feng F, Qin L, Ji W, Li D, Liang R, Zhang Y, Wang Y, Li M, Wu W, Jin Y, Duan G. Role of angiotensin-converting enzyme 2 in fine particulate matter-induced acute lung injury. THE SCIENCE OF THE TOTAL ENVIRONMENT 2022; 825:153964. [PMID: 35182631 DOI: 10.1016/j.scitotenv.2022.153964] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 02/14/2022] [Accepted: 02/14/2022] [Indexed: 06/14/2023]
Abstract
Fine particulate matter (PM2.5) pollution poses significant health concerns worldwide and can cause respiratory diseases. However, how it causes health problems is still poorly understood. Angiotensin-converting enzyme (ACE)2 is a terminal carboxypeptidase implicated in the functions of renin-angiotensin system (RAS) and plays a crucial role in the control of lung inflammation. To investigate whether ACE2 functions in PM2.5-induced lung inflammation, wild-type (WT) C57BL/6J mice and ACE2 knock-out (KO) mice were intratracheally instilled with PBS or PM2.5 suspension for 3 consecutive days, respectively. The concentrations of cytokines in bronchoalveolar lavage fluid (BALF) were determined by ELISA. The expression of ACE2 and ACE and activation of inflammatory signaling pathways in lung tissues were evaluated by immunofluorescence staining and Western blotting. We found that PM2.5 exposure increased ACE2 expression. Loss of ACE2 significantly elevated the levels of total proteins, total cells, and the concentrations of MCP-1, IL-1β in BALF after PM2.5 challenge. Additionally, loss of ACE2 enhanced lung pathologies, airway resistance, and inflammatory signaling activation. Collectively, loss of ACE2 exacerbates PM2.5-induced acute lung injury in mice.
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Affiliation(s)
- Peiyu Zhu
- College of Public Health, Zhengzhou University, Zhengzhou 450001, China; Henan Key Laboratory of Molecular Medicine, Zhengzhou University, Zhengzhou 450001, China
| | - Wenfen Zhang
- Center of Advanced Analysis and Computational Science, Key Laboratory of Molecular Sensing and Harmful Substances Detection Technology, Zhengzhou University, Zhengzhou 450001, China
| | - Feifei Feng
- College of Public Health, Zhengzhou University, Zhengzhou 450001, China
| | - Luwei Qin
- Henan Province Center for Disease Control and Prevention, Zhengzhou 450016, China
| | - Wangquan Ji
- College of Public Health, Zhengzhou University, Zhengzhou 450001, China
| | - Dong Li
- College of Public Health, Zhengzhou University, Zhengzhou 450001, China
| | - Ruonan Liang
- College of Public Health, Zhengzhou University, Zhengzhou 450001, China
| | - Yu Zhang
- College of Public Health, Zhengzhou University, Zhengzhou 450001, China
| | - Yuexia Wang
- College of Public Health, Zhengzhou University, Zhengzhou 450001, China
| | - Mengyuan Li
- College of Public Health, Zhengzhou University, Zhengzhou 450001, China
| | - Weidong Wu
- School of Public Health, Xinxiang Medical University, Xinxiang 453003, Henan, China
| | - Yuefei Jin
- College of Public Health, Zhengzhou University, Zhengzhou 450001, China.
| | - Guangcai Duan
- College of Public Health, Zhengzhou University, Zhengzhou 450001, China; Henan Key Laboratory of Molecular Medicine, Zhengzhou University, Zhengzhou 450001, China.
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40
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Haidar MA, Shakkour Z, Reslan MA, Al-Haj N, Chamoun P, Habashy K, Kaafarani H, Shahjouei S, Farran SH, Shaito A, Saba ES, Badran B, Sabra M, Kobeissy F, Bizri M. SARS-CoV-2 involvement in central nervous system tissue damage. Neural Regen Res 2022; 17:1228-1239. [PMID: 34782556 PMCID: PMC8643043 DOI: 10.4103/1673-5374.327323] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 06/30/2021] [Accepted: 07/28/2021] [Indexed: 12/18/2022] Open
Abstract
As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread globally, it became evident that the SARS-CoV-2 virus infects multiple organs including the brain. Several clinical studies revealed that patients with COVID-19 infection experience an array of neurological signs ranging in severity from headaches to life-threatening strokes. Although the exact mechanism by which the SARS-CoV-2 virus directly impacts the brain is not fully understood, several theories have been suggested including direct and indirect pathways induced by the virus. One possible theory is the invasion of SARS-CoV-2 to the brain occurs either through the bloodstream or via the nerve endings which is considered to be the direct route. Such findings are based on studies reporting the presence of viral material in the cerebrospinal fluid and brain cells. Nevertheless, the indirect mechanisms, including blood-clotting abnormalities and prolonged activation of the immune system, can result in further tissue and organ damages seen during the course of the disease. This overview attempts to give a thorough insight into SARS-CoV-2 coronavirus neurological infection and highlights the possible mechanisms leading to the neurological manifestations observed in infected patients.
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Affiliation(s)
- Muhammad Ali Haidar
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Zaynab Shakkour
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Mohammad Amine Reslan
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Nadine Al-Haj
- Faculty of Health Sciences, University of Balamand, Beirut, Lebanon
| | - Perla Chamoun
- Faculty of Medicine, University of Balamand, Koura, Lebanon
| | - Karl Habashy
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | | | - Shima Shahjouei
- Program for Neurotrauma, Neuroproteomics & Biomarkers Research, Departments of Emergency Medicine, University of Florida, Gainesville, FL, USA
| | - Sarah H. Farran
- Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | | | - Esber S. Saba
- Department of Experimental Pathology, Immunology and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Bassam Badran
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Lebanese University, Hadath, Beirut, Lebanon
| | - Mirna Sabra
- Faculty of Medicine, Lebanese University, Neuroscience Research Center (NRC), Beirut, Lebanon
| | - Firas Kobeissy
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- Neuroscience Institute, Neurology Department, Geisinger Health System, PA, USA
| | - Maya Bizri
- Department of Psychiatry, American University of Beirut, Beirut, Lebanon
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Abdel-Hakeem EA, Abdel Hafez SMN, Kamel BA, Abdel-Hamid HA. Angiotensin 1-7 mitigates rhabdomyolysis induced renal injury in rats via modulation of TLR-4/NF-kB/iNOS and Nrf-2/heme‑oxygenase-1 signaling pathways. Life Sci 2022; 303:120678. [PMID: 35654118 DOI: 10.1016/j.lfs.2022.120678] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 05/13/2022] [Accepted: 05/27/2022] [Indexed: 12/21/2022]
Abstract
AIMS Rhabdomyolysis (RM) is a critical condition with a high mortality rate, but effective management is still deficient. Till date, there are no studies that have addressed the effect of angiotensin 1-7 in this condition, hence, the rationale of this study was to evaluate the potential protective effect of Angiotensin 1-7 (Ang1-7), on rhabdomyolysis (RM) induced kidney injury in rats and detecting the underlying mechanistic insights. MAIN METHODS Forty adult male albino rats were divided into groups; the control group, RM group, RM+Ang1-7 group, and RM+Ang1-7+ A779 group. Sera and urine samples were collected for analysis of renal and muscle injury markers. Kidney tissues were taken for estimation of oxidative, inflammatory, and apoptotic markers as well as angiotensin-II (Ang II) and Ang1-7. Renal histology and expression of inducible nitric oxide synthase-1 (iNOS), real-time PCR for angiotensin-converting enzyme-2 (ACE-2), nuclear erythroid factor-2 (Nrf-2), Toll like receptor 4 (TLR-4) and NF-kB in kidney tissues were also measured. KEY FINDINGS Induction of RM caused renal oxidative stress injury, inflammation, apoptosis and marked deterioration in kidney functions as well as reduction of Ang1-7 and raised Angiotensin-II level in kidney tissues. Administration of Ang1-7 to the RM group reversed all the affected parameters which were blocked by A779 administration (Mas receptor blocker). SIGNIFICANCE We concluded that Ang1-7 could be a potential therapeutic agent that could mitigate RM-induced renal injury. The underlying mechanisms may involve Stimulation of the ACE-2/Ang1-7/MasR axis and modulation of TLR-4/NF-kB/iNOS and Nrf-2/heme‑oxygenase -1 pathways.
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Affiliation(s)
- Elshymaa A Abdel-Hakeem
- Department of Medical Physiology, Faculty of Medicine, Minia University, 61111 Minia, Egypt.
| | | | - Bothina A Kamel
- Department of Biochemistry, Faculty of Medicine, Minia University, 61111 Minia, Egypt
| | - Heba A Abdel-Hamid
- Department of Medical Physiology, Faculty of Medicine, Minia University, 61111 Minia, Egypt
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Qiao Z, Wang J, He Z, Pan L, Feng K, Peng X, Lin Q, Gao Y, Song M, Cao S, Chen Y, Cao Y, Liu G. A Novel Angiotensin I-Converting Enzyme Inhibitory Peptide Derived From Goat Milk Casein Hydrolysate Modulates Angiotensin II-Stimulated Effects on Vascular Smooth Muscle Cells. Front Nutr 2022; 9:878768. [PMID: 35479750 PMCID: PMC9037752 DOI: 10.3389/fnut.2022.878768] [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: 02/18/2022] [Accepted: 03/14/2022] [Indexed: 11/28/2022] Open
Abstract
Hypertension is a major risk factor leading to cardiovascular disease, and is frequently treated with angiotensin I-converting enzyme (ACE) inhibitory peptides. The objective of this study was to separate and identify an ACE-inhibitory peptide from goat milk casein hydrolysates, and to evaluate its potential for improving angiotensin II (Ang II)-mediated adverse effects on vascular smooth muscle cells (VSMCs). A novel ACE-inhibitory peptide with the highest activity from the goat milk casein hydrolysates as determined by four steps of RP-HPLC was purified and identified as Phe-Pro-Gln-Tyr-Leu-Gln-Tyr-Pro-Tyr (FPQYLQYPY). The results of inhibitory kinetics studies indicated that the peptide was a non-competitive inhibitor against ACE. Gastrointestinal digest in vitro analysis showed that the hydrolysate of FPQYLQYPY was still active after digestion with gastrointestinal proteases. Moreover, we found that the peptide could significantly inhibit the proliferation and migration of Ang II-stimulated VSMCs. Further transcriptomic analysis revealed that differentially expressed genes (DEGs) were enriched in the cardiovascular disease-related pathways, and that the peptide may have the ability to regulate vascular remodeling. Our findings indicate the potential anti-hypertensive effects of FPQYLQYPY, as well-implicate its role in regulating vascular dysfunction.
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Affiliation(s)
- Zijiao Qiao
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Sciences, South China Agricultural University, Guangzhou, China
| | - Jiaqi Wang
- Ausnutria Dairy (China) Co., Ltd., Changsha, China
| | - Zeqi He
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Sciences, South China Agricultural University, Guangzhou, China
| | - Lina Pan
- Ausnutria Dairy (China) Co., Ltd., Changsha, China
| | - Konglong Feng
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Sciences, South China Agricultural University, Guangzhou, China
| | - Xiaoyu Peng
- Ausnutria Dairy (China) Co., Ltd., Changsha, China
| | - Qianru Lin
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Sciences, South China Agricultural University, Guangzhou, China
| | - Yu Gao
- Ausnutria Dairy (China) Co., Ltd., Changsha, China
| | - Mingyue Song
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Sciences, South China Agricultural University, Guangzhou, China
| | - Sufang Cao
- Ausnutria Dairy (China) Co., Ltd., Changsha, China
| | - Yunjiao Chen
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Sciences, South China Agricultural University, Guangzhou, China
| | - Yong Cao
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Sciences, South China Agricultural University, Guangzhou, China
| | - Guo Liu
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Sciences, South China Agricultural University, Guangzhou, China.,College of Horticulture, South China Agricultural University, Guangzhou, China
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43
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Kilmister EJ, Tan ST. Insights Into Vascular Anomalies, Cancer, and Fibroproliferative Conditions: The Role of Stem Cells and the Renin-Angiotensin System. Front Surg 2022; 9:868187. [PMID: 35574555 PMCID: PMC9091963 DOI: 10.3389/fsurg.2022.868187] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 03/22/2022] [Indexed: 12/15/2022] Open
Abstract
Cells exhibiting embryonic stem cell (ESC) characteristics have been demonstrated in vascular anomalies (VAs), cancer, and fibroproliferative conditions, which are commonly managed by plastic surgeons and remain largely unsolved. The efficacy of the mTOR inhibitor sirolimus, and targeted therapies that block the Ras/BRAF/MEK/ERK1/2 and PI3KCA/AKT/mTOR pathways in many types of cancer and VAs, further supports the critical role of ESC-like cells in the pathogenesis of these conditions. ESC-like cells in VAs, cancer, and fibroproliferative conditions express components of the renin-angiotensin system (RAS) – a homeostatic endocrine signaling cascade that regulates cells with ESC characteristics. ESC-like cells are influenced by the Ras/BRAF/MEK/ERK1/2 and PI3KCA/AKT/mTOR pathways, which directly regulate cellular proliferation and stemness, and interact with the RAS at multiple points. Gain-of-function mutations affecting these pathways have been identified in many types of cancer and VAs, that have been treated with targeted therapies with some success. In cancer, the RAS promotes tumor progression, treatment resistance, recurrence, and metastasis. The RAS modulates cellular invasion, migration, proliferation, and angiogenesis. It also indirectly regulates ESC-like cells via its direct influence on the tissue microenvironment and by its interaction with the immune system. In vitro studies show that RAS inhibition suppresses the hallmarks of cancer in different experimental models. Numerous epidemiological studies show a reduced incidence of cancer and improved survival outcomes in patients taking RAS inhibitors, although some studies have shown no such effect. The discovery of ESC-like cells that express RAS components in infantile hemangioma (IH) underscores the paradigm shift in the understanding of its programmed biologic behavior and accelerated involution induced by β-blockers and angiotensin-converting enzyme inhibitors. The findings of SOX18 inhibition by R-propranolol suggests the possibility of targeting ESC-like cells in IH without β-adrenergic blockade, and its associated side effects. This article provides an overview of the current knowledge of ESC-like cells and the RAS in VAs, cancer, and fibroproliferative conditions. It also highlights new lines of research and potential novel therapeutic approaches for these unsolved problems in plastic surgery, by targeting the ESC-like cells through manipulation of the RAS, its bypass loops and converging signaling pathways using existing low-cost, commonly available, and safe oral medications.
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Affiliation(s)
| | - Swee T. Tan
- Gillies McIndoe Research Institute, Wellington, New Zealand
- Wellington Regional Plastic, Maxillofacial & Burns Unit, Hutt Hospital, Lower Hutt, New Zealand
- Department of Surgery, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia
- *Correspondence: Swee T. Tan
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44
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G protein-coupled receptor Mas induces an inhibitory effect on myocardial infarction-induced myocardial injury. Int J Biol Macromol 2022; 207:72-80. [PMID: 35247425 DOI: 10.1016/j.ijbiomac.2022.02.163] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 09/28/2021] [Accepted: 02/25/2022] [Indexed: 11/22/2022]
Abstract
Myocardial infarction (MI) is the most prevalent disease with high mortality, leading to devastating heart injury. Here, we aimed to explore the effect of MAS1 on the MI-induced myocardial injury. Significantly, we identified that the expression of MAS1 was decreased in the MI rat model and hypoxia and reoxygenation (H/R)-treated H9C2 cells. Hematoxylin & Eosin (H&E) staining revealed that the overexpression of MAS1 notably attenuated MI-related myocardium injury in the MI rat model. Echocardiography analysis revealed that MI inhibited left ventricular ejection fraction (LVEF) and left ventricular fraction shortening (LVFS), whereas the MAS1 overexpression could increase LVEF and LVFS in the MI rats. Meanwhile, the expression of collagen I, collagen III, α-SMA, ANP, and BNP was decreased by MAS1 overexpression in the MI rats. MAS1 attenuated cardiomyocyte apoptosis in vivo and in vitro. Mechanically, the overexpression of MAS1 decreased the expression of PTEN and enhanced the phosphorylation of PI3K and AKT in vivo and in vitro. The overexpression of PTEN and the PI3k inhibitor LY294002 could reverse the MAS1-mediated MI injury. Thus, we conclude that MAS1 inhibits MI-induced myocardial injury by modulating PTEN/PI3K/AKT signaling. Our finding provides new insight into the mechanism by which MAS1 attenuates MI-related cardiac dysfunction.
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45
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Fan H, Liao W, Spaans F, Pasha M, Davidge ST, Wu J. Chicken muscle hydrolysate reduces blood pressure in spontaneously hypertensive rats, upregulates ACE2, and ameliorates vascular inflammation, fibrosis, and oxidative stress. J Food Sci 2022; 87:1292-1305. [PMID: 35166385 DOI: 10.1111/1750-3841.16077] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 01/11/2022] [Accepted: 01/18/2022] [Indexed: 11/28/2022]
Abstract
Spent hens are egg-laying chicken reaching the end of their egg-laying cycle and are seen as a by-product to the egg industry. A spent hen muscle protein hydrolysate prepared by food-grade thermoase PC10F (SPH-T) has previously shown antihypertensive potential. In the present work, we further investigated its antihypertensive effect and underlying mechanisms in spontaneously hypertensive rats. There are three groups: untreated, low dose (250 mg SPH-T/kg/day body weight), and high dose (1,000 mg SPH-T/kg/day body weight). Oral administration of SPH-T over a period of 20 days reduced systolic blood pressure by 25.7 mm Hg (p < 0.001) and 11.9 mm Hg (p < 0.05), respectively, for the high- and low-dose groups. The high-dose treatment decreased the circulating level of angiotensin II (from 25.0 to 5.7 pg/ml) while increased angiotensin-converting enzyme 2 (ACE2) (from 1.3 to 3.3 IU/ml) and angiotensin (1-7) (from 37.0 to 70.1 pg/ml) significantly (p < 0.05). Furthermore, the high-dose group doubled the aortic expression of ACE2 while reduced the expression of angiotensin (Ang) II type 1 receptor (by 35%). Circulating inflammatory cytokines including tumor necrosis factor alpha and monocyte chemoattractant protein-1 as well as vascular inflammatory proteins including inducible nitric oxide synthase and vascular cell adhesion molecule-1 were attenuated by ∼15%-50% by the treatment; nitrosative stress (35%) and type I collagen synthesis (50%) in the aorta were also attenuated significantly (p < 0.05). Moreover, SPH-T possessed an umami taste (no obvious bitter taste) as analyzed by electronic tongue. PRACTICAL APPLICATION: Hypertension is a global health concern, afflicting more than 20% of adults worldwide. Uncovering the antihypertensive effect of spent hen protein hydrolysate underpinned its functional food nutraceutical applications for the prevention and treatment of hypertension.
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Affiliation(s)
- Hongbing Fan
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada.,Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Wang Liao
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada.,Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Floor Spaans
- Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada.,Women and Children's Health Research Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Mazhar Pasha
- Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada.,Women and Children's Health Research Institute, University of Alberta, Edmonton, Alberta, Canada.,Department of Physiology, University of Alberta, Edmonton, Alberta, Canada
| | - Sandra T Davidge
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada.,Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada.,Women and Children's Health Research Institute, University of Alberta, Edmonton, Alberta, Canada.,Department of Physiology, University of Alberta, Edmonton, Alberta, Canada
| | - Jianping Wu
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada.,Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
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Therapeutic peptides: current applications and future directions. Signal Transduct Target Ther 2022; 7:48. [PMID: 35165272 PMCID: PMC8844085 DOI: 10.1038/s41392-022-00904-4] [Citation(s) in RCA: 819] [Impact Index Per Article: 273.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 01/13/2022] [Accepted: 01/17/2022] [Indexed: 02/08/2023] Open
Abstract
Peptide drug development has made great progress in the last decade thanks to new production, modification, and analytic technologies. Peptides have been produced and modified using both chemical and biological methods, together with novel design and delivery strategies, which have helped to overcome the inherent drawbacks of peptides and have allowed the continued advancement of this field. A wide variety of natural and modified peptides have been obtained and studied, covering multiple therapeutic areas. This review summarizes the efforts and achievements in peptide drug discovery, production, and modification, and their current applications. We also discuss the value and challenges associated with future developments in therapeutic peptides.
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47
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Azouz AA, Omar HA, Hersi F, Ali FEM, Hussein Elkelawy AMM. Impact of the ACE2 activator xanthenone on tacrolimus nephrotoxicity: Modulation of uric acid/ERK/p38 MAPK and Nrf2/SOD3/GCLC signaling pathways. Life Sci 2022; 288:120154. [PMID: 34800514 DOI: 10.1016/j.lfs.2021.120154] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 10/30/2021] [Accepted: 11/12/2021] [Indexed: 10/19/2022]
Abstract
AIMS The calcineurin inhibitor tacrolimus is an effective and widely used immunosuppressant after organ transplantation to reduce graft rejection. However, its nephrotoxic effect could compel the patients to treatment discontinuation. The beneficial effects of angiotensin-converting enzyme 2 (ACE2) on the kidney and other organs have been investigated in several studies, but its role in tacrolimus nephrotoxicity still needs to be elucidated. Our study was designed to investigate effects of the ACE2 activator xanthenone on tacrolimus-induced renal injury. MATERIALS AND METHODS Male Wistar rats were administered xanthenone (2 mg/kg) concurrently with tacrolimus (1 mg/kg) for 3 weeks, then blood and kidney tissue samples were collected for biochemical and molecular investigations. KEY FINDINGS Co-administration of xanthenone significantly improved renal functions in tacrolimus-treated rats, where serum creatinine, urea, and uric acid levels were close to those of the normal control. Besides, xanthenone reduced renal angiotensin (ANG) II content, while elevated ANG (1-7). Relative protein expressions of p-ERK/ERK and p-p38 MAPK/p38 MAPK inflammatory signals were downregulated upon xanthenone administration with tacrolimus. In addition, xanthenone reinforced antioxidant defense against tacrolimus by enhancing protein expression of the transcription factor Nrf2 with subsequently increased mRNA expressions of the antioxidants SOD3 and GCLC. SIGNIFICANCE These protective effects of xanthenone could be attributed to ANG II degradation to ANG (1-7) by ACE2 activation resulting in regulated inflammatory and oxidative responses in the kidney. Therefore, administration of xanthenone along with tacrolimus could be a promising therapeutic strategy to reduce the adverse effects and increase the tolerability to tacrolimus immunosuppressive therapy.
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Affiliation(s)
- Amany A Azouz
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
| | - Hany A Omar
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt; Sharjah Institute for Medical Research, University of Sharjah, United Arab Emirates
| | - Fatema Hersi
- Sharjah Institute for Medical Research, University of Sharjah, United Arab Emirates
| | - Fares E M Ali
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt
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The Effects of ATIR Blocker on the Severity of COVID-19 in Hypertensive Inpatients and Virulence of SARS-CoV-2 in Hypertensive hACE2 Transgenic Mice. J Cardiovasc Transl Res 2022; 15:38-48. [PMID: 34973134 PMCID: PMC8720170 DOI: 10.1007/s12265-021-10147-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 06/02/2021] [Indexed: 01/08/2023]
Abstract
Angiotensin-converting enzyme 2 (ACE2) is required for the cellular entry of the severe acute respiratory syndrome coronavirus 2. ACE2, via the Ang-(1-7)-Mas-R axis, is part of the antihypertensive and cardioprotective effects of the renin-angiotensin system. We studied hospitalized COVID-19 patients with hypertension and hypertensive human(h) ACE2 transgenic mice to determine the outcome of COVID-19 with or without AT1 receptor (AT1R) blocker treatment. The severity of the illness and the levels of serum cardiac biomarkers (CK, CK-BM, cTnI), as well as the inflammation markers (IL-1, IL-6, CRP), were lesser in hypertensive COVID-19 patients treated with AT1R blockers than those treated with other antihypertensive drugs. Hypertensive hACE2 transgenic mice, pretreated with AT1R blocker, had increased ACE2 expression and SARS-CoV-2 in the kidney and heart, 1 day post-infection. We conclude that those hypertensive patients treated with AT1R blocker may be at higher risk for SARS-CoV-2 infection. However, AT1R blockers had no effect on the severity of the illness but instead may have protected COVID-19 patients from heart injury, via the ACE2-angiotensin1-7-Mas receptor axis.
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Shenoy S. Gut microbiome, Vitamin D, ACE2 interactions are critical factors in immune-senescence and inflammaging: key for vaccine response and severity of COVID-19 infection. Inflamm Res 2022; 71:13-26. [PMID: 34738147 PMCID: PMC8568567 DOI: 10.1007/s00011-021-01510-w] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 09/21/2021] [Accepted: 09/23/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The SARS-CoV-2 pandemic continues to spread sporadically in the Unites States and worldwide. The severity and mortality excessively affected the frail elderly with co-existing medical diseases. There is growing evidence that cross-talk between the gut microbiome, Vitamin D and RAS/ACE2 system is essential for a balanced functioning of the elderly immune system and in regulating inflammation. In this review, we hypothesize that the state of gut microbiome, prior to infection determines the outcome associated with COVID-19 sepsis and may also be a critical factor in success to vaccination. METHODS Articles from PubMed/Medline searches were reviewed using a combination of terms "SARS-CoV-2, COVID-19, Inflammaging, Immune-senescence, Gut microbiome, Vitamin D, RAS/ACE2, Vaccination". CONCLUSION Evidence indicates a complex association between gut microbiota, ACE-2 expression and Vitamin D in COVID-19 severity. Status of gut microbiome is highly predictive of the blood molecular signatures and inflammatory markers and host responses to infection. Vitamin D has immunomodulatory function in innate and adaptive immune responses to viral infection. Anti-inflammatory functions of Vit D include regulation of gut microbiome and maintaining microbial diversity. It promotes growth of gut-friendly commensal strains of Bifida and Fermicutus species. In addition, Vitamin D is a negative regulator for expression of renin and interacts with the RAS/ ACE/ACE-2 signaling axis. Collectively, this triad may be the critical, link in determination of outcomes in SARS-CoV-2 infection. The presented data are empirical and informative. Further research using advanced systems biology techniques and artificial intelligence-assisted integration could assist with correlation of the gut microbiome with sepsis and vaccine responses. Modulating these factors may impact in guiding the success of vaccines and clinical outcomes in COVID-19 infections.
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Affiliation(s)
- Santosh Shenoy
- Department of Surgery, Kansas City VA Medical Center, University of Missouri Kansas City, 4801 E Linwood Blvd., Kansas City , MO, 64128, USA.
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Li Y, Jiang S, Gao H, Yang Y, Liu X, Li W. Factors associated with the progression of mesangial lesions in IgA nephropathy: A comparative analysis of renal re-biopsies. Front Endocrinol (Lausanne) 2022; 13:1004289. [PMID: 36479219 PMCID: PMC9719920 DOI: 10.3389/fendo.2022.1004289] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 11/04/2022] [Indexed: 11/22/2022] Open
Abstract
OBJECTIVES IgA nephropathy (IgAN) is the most common primary glomerular disease, and is the leading cause of chronic renal failure. Because mesangial lesions are the main pathological changes seen in IgAN, we investigated factors associated with the progression of mesangial lesions in IgAN. METHODS We enrolled participants with IgAN who underwent repeat renal biopsies. Based on the progression of mesangial proliferative lesions, the participants were divided into progressive and stable groups. The progression group included participants with a ratio of mesangial cell proliferation score ≥ 1.1 (i.e., proliferation of > 10%) in the second biopsy specimen compared to the first biopsy specimen. The stable group included participants who did not fulfill the aforementioned criteria. We recorded the laboratory parameters, expression of renin-angiotensin system (RAS) receptors (angiotensin II type 1 receptor [AT1R], angiotensin II type 2 receptor [AT2R], Mas receptor [MasR], and the Mas-related G protein-coupled receptor, member D [MrgD]) and mesangial matrix proteins (collagen [Col] IV, fibronectin [FN] and laminin) at the first and second renal biopsies, and the use of immunosuppressive therapy and/or RAS blockers after the first biopsy. RESULTS We enrolled 24 patients with IgAN who underwent repeat renal biopsies. Half of patients showed progression of mesangial lesions on repeat renal biopsy after a median of 4.3 (1-6) years. The progression group had significantly higher expression levels of AT1R and mesangial matrix proteins (Col IV and FN), and significantly lower expression of AT2R and MasR, compared to the stable group. Multivariate analysis showed that the use of RAS blockers (hazard ratio [HR], 0.27; 95% CI, 0.08-0.97; p < 0.05) and the level of proteinuria (HR, 1.8; 95% CI, 1.04-3.12; p < 0.05) were associated with progression of mesangial lesions. Additionally, the progression group exhibited a more rapid decline of renal function compared to the stable group (0.38 and 0.012 ml/min/1.73 m2/month, respectively; p = 0.004). CONCLUSIONS Continuous activation of the intrarenal RAS and massive proteinuria correlate with histological progression of mesangial lesions in IgAN patients, which may further accelerate the deterioration of renal function.
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Affiliation(s)
- Yetong Li
- Department of Nephrology, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
| | - Shimin Jiang
- Department of Nephrology, China-Japan Friendship Hospital, Beijing, China
| | - Hongmei Gao
- Department of Nephrology, China-Japan Friendship Hospital, Beijing, China
| | - Yue Yang
- Department of Nephrology, China-Japan Friendship Hospital, Beijing, China
| | - Xiaorong Liu
- Department of Nephrology, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
- *Correspondence: Xiaorong Liu, ; Wenge Li,
| | - Wenge Li
- Department of Nephrology, China-Japan Friendship Hospital, Beijing, China
- *Correspondence: Xiaorong Liu, ; Wenge Li,
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