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Guldan M, Unlu S, Abdel-Rahman SM, Ozbek L, Gaipov A, Covic A, Soler MJ, Covic A, Kanbay M. Understanding the Role of Sex Hormones in Cardiovascular Kidney Metabolic Syndrome: Toward Personalized Therapeutic Approaches. J Clin Med 2024; 13:4354. [PMID: 39124622 PMCID: PMC11312746 DOI: 10.3390/jcm13154354] [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: 07/03/2024] [Revised: 07/18/2024] [Accepted: 07/22/2024] [Indexed: 08/12/2024] Open
Abstract
Cardiovascular kidney metabolic (CKM) syndrome represents a complex interplay of cardiovascular disease (CVD), chronic kidney disease (CKD), and metabolic comorbidities, posing a significant public health challenge. Gender exerts a critical influence on CKM syndrome, affecting the disease severity and onset through intricate interactions involving sex hormones and key physiological pathways such as the renin-angiotensin system, oxidative stress, inflammation, vascular disease and insulin resistance. It is widely known that beyond the contribution of traditional risk factors, men and women exhibit significant differences in CKM syndrome and its components, with distinct patterns observed in premenopausal women and postmenopausal women compared to men. Despite women generally experiencing a lower incidence of CVD, their outcomes following cardiovascular events are often worse compared to men. The disparities also extend to the treatment approaches for kidney failure, with a higher prevalence of dialysis among men despite women exhibiting higher rates of CKD. The impact of endogenous sex hormones, the correlations between CKM and its components, as well as the long-term effects of treatment modalities using sex hormones, including hormone replacement therapies and gender-affirming therapies, have drawn attention to this topic. Current research on CKM syndrome is hindered by the scarcity of large-scale studies and insufficient integration of gender-specific considerations into treatment strategies. The underlying mechanisms driving the gender disparities in the pathogenesis of CKM syndrome, including the roles of estrogen, progesterone and testosterone derivatives, remain poorly understood, thus limiting their application in personalized therapeutic interventions. This review synthesizes existing knowledge to clarify the intricate relationship between sex hormones, gender disparities, and the progression of CVD within CKM syndrome. By addressing these knowledge gaps, this study aims to guide future research efforts and promote tailored approaches for effectively managing CKD syndrome.
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Affiliation(s)
- Mustafa Guldan
- Department of Medicine, Koç University School of Medicine, 34450 Istanbul, Turkey; (M.G.); (S.U.); (S.M.A.-R.); (L.O.)
| | - Selen Unlu
- Department of Medicine, Koç University School of Medicine, 34450 Istanbul, Turkey; (M.G.); (S.U.); (S.M.A.-R.); (L.O.)
| | - Sama Mahmoud Abdel-Rahman
- Department of Medicine, Koç University School of Medicine, 34450 Istanbul, Turkey; (M.G.); (S.U.); (S.M.A.-R.); (L.O.)
| | - Laşin Ozbek
- Department of Medicine, Koç University School of Medicine, 34450 Istanbul, Turkey; (M.G.); (S.U.); (S.M.A.-R.); (L.O.)
| | - Abduzhappar Gaipov
- Department of Medicine, School of Medicine, Nazarbayev University, Astana 010000, Kazakhstan;
| | - Andreea Covic
- Department of Nephrology, Grigore T. Popa University of Medicine, 700115 Iasi, Romania;
| | - Maria José Soler
- Nephrology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Research, 08035 Barcelona, Spain;
- Centro de Referencia en Enfermedad, Glomerular Compleja del Sistema Nacional de Salud de España (CSUR), RICORS2040 (Kidney Disease), 08003 Barcelona, Spain
- GEENDIAB (Grupo Español de Estudio de la Nefropatía Diabética), 39008 Santander, Spain
| | - Adrian Covic
- Department of Nephrology, Grigore T. Popa University of Medicine, 700115 Iasi, Romania;
| | - Mehmet Kanbay
- Division of Nephrology, Department of Medicine, Koç University School of Medicine, 34450 Istanbul, Turkey;
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Scott SR, Singh K, Yu Q, Sen CK, Wang M. Sex as Biological Variable in Cardiac Mitochondrial Bioenergetic Responses to Acute Stress. Int J Mol Sci 2022; 23:9312. [PMID: 36012574 PMCID: PMC9409303 DOI: 10.3390/ijms23169312] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/10/2022] [Accepted: 08/17/2022] [Indexed: 11/29/2022] Open
Abstract
Cardiac dysfunction/damage following trauma, shock, sepsis, and ischemia impacts clinical outcomes. Acute inflammation and oxidative stress triggered by these injuries impair mitochondria, which are critical to maintaining cardiac function. Despite sex dimorphisms in consequences of these injuries, it is unclear whether mitochondrial bioenergetic responses to inflammation/oxidative stress are sex-dependent. We hypothesized that sex disparity in mitochondrial bioenergetics following TNFα or H2O2 exposure is responsible for reported sex differences in cardiac damage/dysfunction. Methods and Results: Cardiomyocytes isolated from age-matched adult male and female mice were subjected to 1 h TNFα or H2O2 challenge, followed by detection of mitochondrial respiration capacity using the Seahorse XF96 Cell Mito Stress Test. Mitochondrial membrane potential (ΔΨm) was analyzed using JC-1 in TNFα-challenged cardiomyocytes. We found that cardiomyocytes isolated from female mice displayed a better mitochondrial bioenergetic response to TNFα or H2O2 than those isolated from male mice did. TNFα decreased ΔΨm in cardiomyocytes isolated from males but not from females. 17β-estradiol (E2) treatment improved mitochondrial metabolic function in cardiomyocytes from male mice subjected to TNFα or H2O2 treatment. Conclusions: Cardiomyocyte mitochondria from female mice were more resistant to acute stress than those from males. The female sex hormone E2 treatment protected cardiac mitochondria against acute inflammatory and oxidative stress.
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Affiliation(s)
- Susan R. Scott
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Kanhaiya Singh
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Qing Yu
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Chandan K. Sen
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Meijing Wang
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Lee Y, Singh J, Scott SR, Ellis B, Zorlutuna P, Wang M. A Recombinant Dimethylarginine Dimethylaminohydrolase-1-Based Biotherapeutics to Pharmacologically Lower Asymmetric Dimethyl Arginine, thus Improving Postischemic Cardiac Function and Cardiomyocyte Mitochondrial Activity. Mol Pharmacol 2022; 101:226-235. [PMID: 35042831 PMCID: PMC11033929 DOI: 10.1124/molpharm.121.000394] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 01/16/2022] [Indexed: 11/22/2022] Open
Abstract
High serum levels of asymmetric dimethyl arginine (ADMA) are associated with cardiovascular disease and mortality. Pharmacological agents to specifically lower ADMA and their potential impact on cardiovascular complications are not known. In this study, we aimed to investigate the effect of specific lowering of ADMA on myocardial response to ischemia-reperfusion injury (I/R) and direct effects on cardiomyocyte function. Effects of recombinant dimethylarginine dimethylaminohydrolase (rDDAH)-1 on I/R injury were determined using isolated mouse heart preparation. Respiration capacity and mitochondrial reactive oxygen species (ROS) generation were determined on mouse cardiomyocytes. Our results show that lowering ADMA by rDDAH-1 treatment resulted in improved recovery of cardiac function and reduction in myocardial infarct size in mouse heart response to I/R injury (control 22.24 ±4.60% versus rDDAH-1 15.90 ±4.23%, P < 0.01). In mouse cardiomyocytes, rDDAH-1 treatment improved ADMA-induced dysregulation of respiration capacity and decreased mitochondrial ROS. Furthermore, in human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes with impaired contractility under hypoxia and high ADMA, rDDAH-1 treatment improved recovery and beating frequency (P < 0.05). rDDAH-1 treatment selectively modified I/R-induced myocardial cytokine expression, resulting in reduction in proinflammatory cytokine IL-17A (P < 0.001) and increased expression of anti-inflammatory cytokines IL-10 and IL-13 (P < 0.01). Further in vitro studies showed that IL-17A was the predominant and common cytokine modulated by ADMA-DDAH pathway in heart, cardiomyocytes, and endothelial cells. These studies show that lowering ADMA by pharmacological treatment with rDDAH-1 reduced I/R injury, improved cardiac function, and ameliorated cardiomyocyte bioenergetics and beating activity. These effects may be attributable to ADMA lowering in cardiomyocytes and preservation of cardiomyocyte mitochondrial function. SIGNIFICANCE STATEMENT: The pathological role of asymmetric dimethyl arginine (ADMA) has been demonstrated by its association with cardiovascular disease and mortality. Currently, pharmacological drugs to specifically lower ADMA are not available. The present study provides the first evidence that lowering of ADMA by recombinant recombinant dimethylarginine dimethylaminohydrolase (rDDAH)-1 improved postischemic cardiac function and cardiomyocyte bioenergetics and beating activity. Our studies suggest that lowering of ADMA by pharmacologic treatment offers opportunity to develop new therapies for the treatment of cardiovascular and renal disease.
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Affiliation(s)
- Young Lee
- Indiana Center for Biomedical Innovation, Indianapolis, Indiana (Y.L., J.S.); Indiana University School of Medicine, Indianapolis, Indiana (J.S.); Department of Surgery, Indiana University, School of Medicine, Indianapolis, Indiana (S.R.S., M.W.); Bioengineering Graduate Program (B.E., P.Z.) and Aerospace and Mechanical Engineering Department (P.Z.), University of Notre Dame, Notre Dame, Indiana; and Vasculonics LLC, Indianapolis, Indiana (J.S.)
| | - Jaipal Singh
- Indiana Center for Biomedical Innovation, Indianapolis, Indiana (Y.L., J.S.); Indiana University School of Medicine, Indianapolis, Indiana (J.S.); Department of Surgery, Indiana University, School of Medicine, Indianapolis, Indiana (S.R.S., M.W.); Bioengineering Graduate Program (B.E., P.Z.) and Aerospace and Mechanical Engineering Department (P.Z.), University of Notre Dame, Notre Dame, Indiana; and Vasculonics LLC, Indianapolis, Indiana (J.S.)
| | - Susan R Scott
- Indiana Center for Biomedical Innovation, Indianapolis, Indiana (Y.L., J.S.); Indiana University School of Medicine, Indianapolis, Indiana (J.S.); Department of Surgery, Indiana University, School of Medicine, Indianapolis, Indiana (S.R.S., M.W.); Bioengineering Graduate Program (B.E., P.Z.) and Aerospace and Mechanical Engineering Department (P.Z.), University of Notre Dame, Notre Dame, Indiana; and Vasculonics LLC, Indianapolis, Indiana (J.S.)
| | - Bradley Ellis
- Indiana Center for Biomedical Innovation, Indianapolis, Indiana (Y.L., J.S.); Indiana University School of Medicine, Indianapolis, Indiana (J.S.); Department of Surgery, Indiana University, School of Medicine, Indianapolis, Indiana (S.R.S., M.W.); Bioengineering Graduate Program (B.E., P.Z.) and Aerospace and Mechanical Engineering Department (P.Z.), University of Notre Dame, Notre Dame, Indiana; and Vasculonics LLC, Indianapolis, Indiana (J.S.)
| | - Pinar Zorlutuna
- Indiana Center for Biomedical Innovation, Indianapolis, Indiana (Y.L., J.S.); Indiana University School of Medicine, Indianapolis, Indiana (J.S.); Department of Surgery, Indiana University, School of Medicine, Indianapolis, Indiana (S.R.S., M.W.); Bioengineering Graduate Program (B.E., P.Z.) and Aerospace and Mechanical Engineering Department (P.Z.), University of Notre Dame, Notre Dame, Indiana; and Vasculonics LLC, Indianapolis, Indiana (J.S.)
| | - Meijing Wang
- Indiana Center for Biomedical Innovation, Indianapolis, Indiana (Y.L., J.S.); Indiana University School of Medicine, Indianapolis, Indiana (J.S.); Department of Surgery, Indiana University, School of Medicine, Indianapolis, Indiana (S.R.S., M.W.); Bioengineering Graduate Program (B.E., P.Z.) and Aerospace and Mechanical Engineering Department (P.Z.), University of Notre Dame, Notre Dame, Indiana; and Vasculonics LLC, Indianapolis, Indiana (J.S.)
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Wang M, Yan L, Li Q, Yang Y, Turrentine M, March K, Wang IW. Mesenchymal stem cell secretions improve donor heart function following ex vivo cold storage. J Thorac Cardiovasc Surg 2022; 163:e277-e292. [PMID: 32981709 PMCID: PMC7921217 DOI: 10.1016/j.jtcvs.2020.08.095] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 08/15/2020] [Accepted: 08/24/2020] [Indexed: 12/20/2022]
Abstract
OBJECTIVES Heart transplantation is the gold standard of treatments for end-stage heart failure, but its use is limited by extreme shortage of donor organs. The time "window" between procurement and transplantation sets the stage for myocardial ischemia/reperfusion injury, which constrains the maximal storage time and lowers use of donor organs. Given mesenchymal stem cell (MSC)-derived paracrine protection, we aimed to evaluate the efficacy of MSC-conditioned medium (CM) and extracellular vesicles (EVs) when added to ex vivo preservation solution on ameliorating ischemia/reperfusion-induced myocardial damage in donor hearts. METHODS Mouse donor hearts were stored at 0°C-4°C of <1-hour cold ischemia (<1hr-I), 6hr-I + vehicle, 6hr-I + MSC-CM, 6hr-I + MSC-EVs, and 6hr-I + MSC-CM from MSCs treated with exosome release inhibitor. The hearts were then heterotopically implanted into recipient mice. At 24 hours postsurgery, myocardial function was evaluated. Heart tissue was collected for analysis of histology, apoptotic cell death, microRNA (miR)-199a-3p expression, and myocardial cytokine production. RESULTS Six-hour cold ischemia significantly impaired myocardial function, increased cell death, and reduced miR-199a-3p in implanted hearts versus <1hr-I. MSC-CM or MSC-EVs in preservation solution reversed the detrimental effects of prolong cold ischemia on donor hearts. Exosome-depleted MSC-CM partially abolished MSC secretome-mediated cardioprotection in implanted hearts. MiR-199a-3p was highly enriched in MSC-EVs. MSC-CM and MSC-EVs increased cold ischemia-downregulated miR-199a-3p in donor hearts, whereas exosome-depletion neutralized this effect. CONCLUSIONS MSC-CM and MSC-EVs confer improved myocardial preservation in donor hearts during prolonged cold static storage and MSC-EVs can be used for intercellular transport of miRNAs in heart transplantation.
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Affiliation(s)
- Meijing Wang
- Division of Cardiothoracic Surgery, Department of Surgery, IU School of Medicine, Indianapolis, Ind.
| | - Liangliang Yan
- Division of Cardiothoracic Surgery, Department of Surgery, IU School of Medicine, Indianapolis, Ind; Department of Cardiovascular Surgery, Fujian Medical University Union Hospital, Fujian, China
| | - Qianzhen Li
- Division of Cardiothoracic Surgery, Department of Surgery, IU School of Medicine, Indianapolis, Ind; Department of Cardiovascular Surgery, Fujian Medical University Union Hospital, Fujian, China; Division of Cardiovascular Medicine, Department of Medicine, IU School of Medicine, Indianapolis, Ind
| | - Yang Yang
- Division of Cardiothoracic Surgery, Department of Surgery, IU School of Medicine, Indianapolis, Ind
| | - Mark Turrentine
- Division of Cardiothoracic Surgery, Department of Surgery, IU School of Medicine, Indianapolis, Ind
| | - Keith March
- Division of Cardiovascular Medicine, Department of Medicine, IU School of Medicine, Indianapolis, Ind; Division of Cardiovascular Medicine, Center for Regenerative Medicine, University of Florida, Gainesville, Fla
| | - I-Wen Wang
- Division of Cardiothoracic Surgery, Department of Surgery, IU School of Medicine, Indianapolis, Ind; Methodist Hospital, IU Health, IU School of Medicine, Indianapolis, Ind.
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Sex-Related Effects on Cardiac Development and Disease. J Cardiovasc Dev Dis 2022; 9:jcdd9030090. [PMID: 35323638 PMCID: PMC8949052 DOI: 10.3390/jcdd9030090] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 03/16/2022] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality. Interestingly, male and female patients with CVD exhibit distinct epidemiological and pathophysiological characteristics, implying a potentially important role for primary and secondary sex determination factors in heart development, aging, disease and therapeutic responses. Here, we provide a concise review of the field and discuss current gaps in knowledge as a step towards elucidating the “sex determination–heart axis”. We specifically focus on cardiovascular manifestations of abnormal sex determination in humans, such as in Turner and Klinefelter syndromes, as well as on the differences in cardiac regenerative potential between species with plastic and non-plastic sexual phenotypes. Sex-biased cardiac repair mechanisms are also discussed with a focus on the role of the steroid hormone 17β-estradiol. Understanding the “sex determination–heart axis” may offer new therapeutic possibilities for enhanced cardiac regeneration and/or repair post-injury.
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Scott SR, March KL, Wang IW, Singh K, Liu J, Turrentine M, Sen CK, Wang M. Bone marrow- or adipose-mesenchymal stromal cell secretome preserves myocardial transcriptome profile and ameliorates cardiac damage following ex vivo cold storage. J Mol Cell Cardiol 2022; 164:1-12. [PMID: 34774548 PMCID: PMC8860861 DOI: 10.1016/j.yjmcc.2021.11.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 10/24/2021] [Accepted: 11/03/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Heart transplantation, a life-saving approach for patients with end-stage heart disease, is limited by shortage of donor organs. While prolonged storage provides more organs, it increases the extent of ischemia. Therefore, we seek to understand molecular mechanisms underlying pathophysiological changes of donor hearts during prolonged storage. Additionally, considering mesenchymal stromal cell (MSC)-derived paracrine protection, we aim to test if MSC secretome preserves myocardial transcriptome profile and whether MSC secretome from a certain source provides the optimal protection in donor hearts during cold storage. METHODS AND RESULTS Isolated mouse hearts were divided into: no cold storage (control), 6 h cold storage (6 h-I), 6 h-I + conditioned media from bone marrow MSCs (BM-MSC CM), and 6 h-I + adipose-MSC CM (Ad-MSC CM). Deep RNA sequencing analysis revealed that compared to control, 6 h-I led to 266 differentially expressed genes, many of which were implicated in modulating mitochondrial performance, oxidative stress response, myocardial function, and apoptosis. BM-MSC CM and Ad-MSC CM restored these gene expression towards control. They also improved 6 h-I-induced myocardial functional depression, reduced inflammatory cytokine production, decreased apoptosis, and reduced myocardial H2O2. However, neither MSC-exosomes nor exosome-depleted CM recapitulated MSC CM-ameliorated apoptosis and CM-improved mitochondrial preservation during cold ischemia. Knockdown of Per2 by specific siRNA abolished MSC CM-mediated these protective effects in cardiomyocytes following 6 h cold storage. CONCLUSIONS Our results demonstrated that using MSC secretome (BM-MSCs and Ad-MSCs) during prolonged cold storage confers preservation of the normal transcriptional "fingerprint", and reduces donor heart damage. MSC-released soluble factors and exosomes may synergistically act for donor heart protection.
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Affiliation(s)
- Susan R Scott
- Department of Surgery, IU School of Medicine, Indianapolis, IN, U.S.A
| | - Keith L March
- Division of Cardiovascular Medicine, Department of Medicine, IU School of Medicine, Indianapolis, IN, U.S.A,Division of Cardiovascular Medicine, Center for Regenerative Medicine, University of Florida, Gainesville, FL, U.S.A
| | - I-wen Wang
- Department of Surgery, IU School of Medicine, Indianapolis, IN, U.S.A,Methodist Hospital, IU Health, IU School of Medicine, Indianapolis, IN, U.S.A
| | - Kanhaiya Singh
- Department of Surgery, IU School of Medicine, Indianapolis, IN, U.S.A,Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, Indiana, U.S.A
| | - Jianyun Liu
- Department of Surgery, IU School of Medicine, Indianapolis, IN, U.S.A
| | - Mark Turrentine
- Department of Surgery, IU School of Medicine, Indianapolis, IN, U.S.A
| | - Chandan K Sen
- Department of Surgery, IU School of Medicine, Indianapolis, IN, U.S.A,Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, Indiana, U.S.A
| | - Meijing Wang
- Department of Surgery, IU School of Medicine, Indianapolis, IN, USA.
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Mehanna RA, Essawy MM, Barkat MA, Awaad AK, Thabet EH, Hamed HA, Elkafrawy H, Khalil NA, Sallam A, Kholief MA, Ibrahim SS, Mourad GM. Cardiac stem cells: Current knowledge and future prospects. World J Stem Cells 2022; 14:1-40. [PMID: 35126826 PMCID: PMC8788183 DOI: 10.4252/wjsc.v14.i1.1] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 07/02/2021] [Accepted: 01/06/2022] [Indexed: 02/06/2023] Open
Abstract
Regenerative medicine is the field concerned with the repair and restoration of the integrity of damaged human tissues as well as whole organs. Since the inception of the field several decades ago, regenerative medicine therapies, namely stem cells, have received significant attention in preclinical studies and clinical trials. Apart from their known potential for differentiation into the various body cells, stem cells enhance the organ's intrinsic regenerative capacity by altering its environment, whether by exogenous injection or introducing their products that modulate endogenous stem cell function and fate for the sake of regeneration. Recently, research in cardiology has highlighted the evidence for the existence of cardiac stem and progenitor cells (CSCs/CPCs). The global burden of cardiovascular diseases' morbidity and mortality has demanded an in-depth understanding of the biology of CSCs/CPCs aiming at improving the outcome for an innovative therapeutic strategy. This review will discuss the nature of each of the CSCs/CPCs, their environment, their interplay with other cells, and their metabolism. In addition, important issues are tackled concerning the potency of CSCs/CPCs in relation to their secretome for mediating the ability to influence other cells. Moreover, the review will throw the light on the clinical trials and the preclinical studies using CSCs/CPCs and combined therapy for cardiac regeneration. Finally, the novel role of nanotechnology in cardiac regeneration will be explored.
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Affiliation(s)
- Radwa A Mehanna
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Marwa M Essawy
- Oral Pathology Department, Faculty of Dentistry/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Mona A Barkat
- Human Anatomy and Embryology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Ashraf K Awaad
- Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Eman H Thabet
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Heba A Hamed
- Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Hagar Elkafrawy
- Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Nehal A Khalil
- Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Abeer Sallam
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Marwa A Kholief
- Forensic Medicine and Clinical toxicology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Samar S Ibrahim
- Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Ghada M Mourad
- Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt.
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Mehanna RA, Essawy MM, Barkat MA, Awaad AK, Thabet EH, Hamed HA, Elkafrawy H, Khalil NA, Sallam A, Kholief MA, Ibrahim SS, Mourad GM. Cardiac stem cells: Current knowledge and future prospects. World J Stem Cells 2022. [PMID: 35126826 DOI: 10.4252/wjsc.v14.i1.1]] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Regenerative medicine is the field concerned with the repair and restoration of the integrity of damaged human tissues as well as whole organs. Since the inception of the field several decades ago, regenerative medicine therapies, namely stem cells, have received significant attention in preclinical studies and clinical trials. Apart from their known potential for differentiation into the various body cells, stem cells enhance the organ's intrinsic regenerative capacity by altering its environment, whether by exogenous injection or introducing their products that modulate endogenous stem cell function and fate for the sake of regeneration. Recently, research in cardiology has highlighted the evidence for the existence of cardiac stem and progenitor cells (CSCs/CPCs). The global burden of cardiovascular diseases' morbidity and mortality has demanded an in-depth understanding of the biology of CSCs/CPCs aiming at improving the outcome for an innovative therapeutic strategy. This review will discuss the nature of each of the CSCs/CPCs, their environment, their interplay with other cells, and their metabolism. In addition, important issues are tackled concerning the potency of CSCs/CPCs in relation to their secretome for mediating the ability to influence other cells. Moreover, the review will throw the light on the clinical trials and the preclinical studies using CSCs/CPCs and combined therapy for cardiac regeneration. Finally, the novel role of nanotechnology in cardiac regeneration will be explored.
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Affiliation(s)
- Radwa A Mehanna
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Marwa M Essawy
- Oral Pathology Department, Faculty of Dentistry/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Mona A Barkat
- Human Anatomy and Embryology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Ashraf K Awaad
- Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Eman H Thabet
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Heba A Hamed
- Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Hagar Elkafrawy
- Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Nehal A Khalil
- Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Abeer Sallam
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Marwa A Kholief
- Forensic Medicine and Clinical toxicology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Samar S Ibrahim
- Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Ghada M Mourad
- Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt.
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Neugarten J, Golestaneh L. Gender-dependent mechanisms of injury and repair. REGENERATIVE NEPHROLOGY 2022:303-318. [DOI: 10.1016/b978-0-12-823318-4.00023-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Hasan AS, Luo L, Baba S, Li TS. Estrogen is required for maintaining the quality of cardiac stem cells. PLoS One 2021; 16:e0245166. [PMID: 33481861 PMCID: PMC7822545 DOI: 10.1371/journal.pone.0245166] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Accepted: 12/22/2020] [Indexed: 12/24/2022] Open
Abstract
Compared to the age-matched men, the incidence of cardiovascular diseases is lower in premenopausal but higher in postmenopausal women, suggesting the cardio-protective role of estrogen in females. Although cardiac stem cells (CSCs) express estrogen receptors, yet the effects of estrogen on CSCs remain unclear. In this study, we investigated the potential role of estrogen in maintaining the quality of CSCs by in vivo and in vitro experiments. For the in vivo study, estrogen deficiency was induced by ovariectomy in 6-weeks-old C57BL/6 female mice, and then randomly given 17β-estradiol (E2) replacements at a low dose (0.01 mg/60 days) and high dose (0.18 mg/60 days), or vehicle treatment. All mice were killed 2 months after treatments, and heart tissues were collected for ex vivo expansion of CSCs. Compared to age-matched healthy controls, estrogen deficiency slightly decreased the yield of CSCs with significantly lower telomerase activity and more DNA damage. Interestingly, E2 replacements at low and high doses significantly increased the yield of CSCs and reversed the quality impairment of CSCs following estrogen deficiency. For the in vitro study, twice-passaged CSCs from the hearts of adult healthy female mice were cultured with the supplement of 0.01, 0.1, and 1 μM E2 in the medium for 3 days. We found that E2 supplement increased c-kit expression, increased proliferative activity, improved telomerase activity, and reduced DNA damage of CSCs in a dose-dependent manner. Our data suggested the potential role of estrogen in maintaining the quality of CSCs, providing new insight into the cardio-protective effects of estrogen.
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Affiliation(s)
- Al Shaimaa Hasan
- Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan
- Department of Medical Pharmacology, Qena Faculty of Medicine, South Valley University, Qena, Egypt
| | - Lan Luo
- Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan
- School of Medical Technology, Xuzhou Medical University, Xuzhou City, Jiangsu Province, China
| | - Satoko Baba
- Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan
| | - Tao-Sheng Li
- Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan
- * E-mail:
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11
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Wang M, Smith K, Yu Q, Miller C, Singh K, Sen CK. Mitochondrial connexin 43 in sex-dependent myocardial responses and estrogen-mediated cardiac protection following acute ischemia/reperfusion injury. Basic Res Cardiol 2019; 115:1. [PMID: 31741053 DOI: 10.1007/s00395-019-0759-5] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 11/05/2019] [Indexed: 01/23/2023]
Abstract
Preserving mitochondrial activity is crucial in rescuing cardiac function following acute myocardial ischemia/reperfusion (I/R). The sex difference in myocardial functional recovery has been observed after I/R. Given the key role of mitochondrial connexin43 (Cx43) in cardiac protection initiated by ischemic preconditioning, we aimed to determine the implication of mitochondrial Cx43 in sex-related myocardial responses and to examine the effect of estrogen (17β-estradiol, E2) on Cx43, particularly mitochondrial Cx43-involved cardiac protection following I/R. Mouse primary cardiomyocytes and isolated mouse hearts (from males, females, ovariectomized females, and doxycycline-inducible Tnnt2-controlled Cx43 knockout without or with acute post-ischemic E2 treatment) were subjected to simulated I/R in culture or Langendorff I/R (25-min warm ischemia/40-min reperfusion), respectively. Mitochondrial membrane potential and mitochondrial superoxide production were measured in cardiomyocytes. Myocardial function and infarct size were determined. Cx43 and its isoform, Gja1-20k, were assessed in mitochondria. Immunoelectron microscopy and co-immunoprecipitation were also used to examine mitochondrial Cx43 and its interaction with estrogen receptor-α by E2 in mitochondria, respectively. There were sex disparities in stress-induced cardiomyocyte mitochondrial function. E2 partially restored mitochondrial activity in cardiomyocytes following acute injury. Post-ischemia infusion of E2 improved functional recovery and reduced infarct size with increased Cx43 content and phosphorylation in mitochondria. Ablation of cardiac Cx43 aggravated mitochondrial damage and abolished E2-mediated cardiac protection during I/R. Female mice were more resistant to myocardial I/R than age-matched males with greater protective role of mitochondrial Cx43 in female hearts. Post-ischemic E2 usage augmented mitochondrial Cx43 content and phosphorylation, increased mitochondrial Gja1-20k, and showed cardiac protection.
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Affiliation(s)
- Meijing Wang
- Department of Surgery, Indiana University School of Medicine, 950 W. Walnut Street, R2 E319, Indianapolis, IN, 46202, USA.
| | - Kwynlyn Smith
- Department of Surgery, Indiana University School of Medicine, 950 W. Walnut Street, R2 E319, Indianapolis, IN, 46202, USA
| | - Qing Yu
- Department of Surgery, Indiana University School of Medicine, 950 W. Walnut Street, R2 E319, Indianapolis, IN, 46202, USA
| | - Caroline Miller
- Electron Microscopy Center, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Kanhaiya Singh
- Department of Surgery, Indiana University School of Medicine, 950 W. Walnut Street, R2 E319, Indianapolis, IN, 46202, USA.,Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Chandan K Sen
- Department of Surgery, Indiana University School of Medicine, 950 W. Walnut Street, R2 E319, Indianapolis, IN, 46202, USA.,Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, USA
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12
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Fortini F, Vieceli Dalla Sega F, Caliceti C, Lambertini E, Pannuti A, Peiffer DS, Balla C, Rizzo P. Estrogen-mediated protection against coronary heart disease: The role of the Notch pathway. J Steroid Biochem Mol Biol 2019; 189:87-100. [PMID: 30817989 DOI: 10.1016/j.jsbmb.2019.02.008] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 02/05/2019] [Accepted: 02/20/2019] [Indexed: 12/28/2022]
Abstract
Estrogen regulates a plethora of biological processes, under physiological and pathological conditions, by affecting key pathways involved in the regulation of cell proliferation, fate, survival and metabolism. The Notch receptors are mediators of communication between adjacent cells and are key determinants of cell fate during development and in postnatal life. Crosstalk between estrogen and the Notch pathway intervenes in many processes underlying the development and maintenance of the cardiovascular system. The identification of molecular mechanisms underlying the interaction between these types of endocrine and juxtacrine signaling are leading to a deeper understanding of physiological conditions regulated by these steroid hormones and, potentially, to novel therapeutic approaches to prevent pathologies linked to reduced levels of estrogen, such as coronary heart disease, and cardiotoxicity caused by hormone therapy for estrogen-receptor-positive breast cancer.
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Affiliation(s)
| | | | - Cristiana Caliceti
- Department of Chemistry "Giacomo Ciamician", Alma Mater Studiorum-University of Bologna, Bologna, Italy
| | - Elisabetta Lambertini
- Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, Ferrara, Italy
| | - Antonio Pannuti
- University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI, USA
| | - Daniel S Peiffer
- Oncology Research Institute, Loyola University Chicago: Health Sciences Division, Maywood, Illinois, USA; Department of Microbiology and Immunology, Loyola University Chicago: Health Sciences Division, Maywood, Illinois, USA
| | - Cristina Balla
- Cardiovascular Center, University of Ferrara, Ferrara, Italy
| | - Paola Rizzo
- Maria Cecilia Hospital, GVM Care & Research, Cotignola, RA, Italy; Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy; Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
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13
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Puglisi R, Mattia G, Carè A, Marano G, Malorni W, Matarrese P. Non-genomic Effects of Estrogen on Cell Homeostasis and Remodeling With Special Focus on Cardiac Ischemia/Reperfusion Injury. Front Endocrinol (Lausanne) 2019; 10:733. [PMID: 31708877 PMCID: PMC6823206 DOI: 10.3389/fendo.2019.00733] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 10/10/2019] [Indexed: 12/12/2022] Open
Abstract
This review takes into consideration the main mechanisms involved in cellular remodeling following an ischemic injury, with special focus on the possible role played by non-genomic estrogen effects. Sex differences have also been considered. In fact, cardiac ischemic events induce damage to different cellular components of the heart, such as cardiomyocytes, vascular cells, endothelial cells, and cardiac fibroblasts. The ability of the cardiovascular system to counteract an ischemic insult is orchestrated by these cell types and is carried out thanks to a number of complex molecular pathways, including genomic (slow) or non-genomic (fast) effects of estrogen. These pathways are probably responsible for differences observed between the two sexes. Literature suggests that male and female hearts, and, more in general, cardiovascular system cells, show significant differences in many parameters under both physiological and pathological conditions. In particular, many experimental studies dealing with sex differences in the cardiovascular system suggest a higher ability of females to respond to environmental insults in comparison with males. For instance, as cells from females are more effective in counteracting the ischemia/reperfusion injury if compared with males, a role for estrogen in this sex disparity has been hypothesized. However, the possible involvement of estrogen-dependent non-genomic effects on the cardiovascular system is still under debate. Further experimental studies, including sex-specific studies, are needed in order to shed further light on this matter.
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Affiliation(s)
- Rossella Puglisi
- Center for Gender Specific Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Gianfranco Mattia
- Center for Gender Specific Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Alessandra Carè
- Center for Gender Specific Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Giuseppe Marano
- Center for Gender Specific Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Walter Malorni
- Center for Gender Specific Medicine, Istituto Superiore di Sanità, Rome, Italy
- School of Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Paola Matarrese
- Center for Gender Specific Medicine, Istituto Superiore di Sanità, Rome, Italy
- *Correspondence: Paola Matarrese
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14
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Ueda K, Adachi Y, Liu P, Fukuma N, Takimoto E. Regulatory Actions of Estrogen Receptor Signaling in the Cardiovascular System. Front Endocrinol (Lausanne) 2019; 10:909. [PMID: 31998238 PMCID: PMC6965027 DOI: 10.3389/fendo.2019.00909] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 12/12/2019] [Indexed: 01/09/2023] Open
Abstract
Premenopausal females have a lower incidence of death from cardiovascular disease (CVD) than male counterparts, supporting the notion that estrogen is protective against the development and progression of CVD. Although large-scale randomized trials of postmenopausal hormone replacement therapy failed to show cardiovascular benefits, recent ELITE study demonstrated anti-atherosclerotic benefits of exogenous estrogen depending on the initiation timing of the therapy. These results have urged us to better understand the mechanisms for actions of estrogens on CVD. Here, we review experimental and human studies, highlighting the emerging role of estrogen's non-nuclear actions linking to NO-cGMP signaling pathways.
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Affiliation(s)
- Kazutaka Ueda
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yusuke Adachi
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Pangyen Liu
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Nobuaki Fukuma
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Eiki Takimoto
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- *Correspondence: Eiki Takimoto
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15
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Estradiol mediates the long-lasting lung inflammation induced by intestinal ischemia and reperfusion. J Surg Res 2018; 221:1-7. [DOI: 10.1016/j.jss.2017.07.038] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Revised: 07/24/2017] [Accepted: 07/25/2017] [Indexed: 11/23/2022]
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16
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Torán JL, Aguilar S, López JA, Torroja C, Quintana JA, Santiago C, Abad JL, Gomes-Alves P, Gonzalez A, Bernal JA, Jiménez-Borreguero LJ, Alves PM, R-Borlado L, Vázquez J, Bernad A. CXCL6 is an important paracrine factor in the pro-angiogenic human cardiac progenitor-like cell secretome. Sci Rep 2017; 7:12490. [PMID: 28970523 PMCID: PMC5624898 DOI: 10.1038/s41598-017-11976-6] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Accepted: 08/29/2017] [Indexed: 12/22/2022] Open
Abstract
Studies in recent years have established that the principal effects in cardiac cell therapy are associated with paracrine/autocrine factors. We combined several complementary techniques to define human cardiac progenitor cell (CPC) secretome constituted by 914 proteins/genes; 51% of these are associated with the exosomal compartment. To define the set of proteins specifically or highly differentially secreted by CPC, we compared human mesenchymal stem cells and dermal fibroblasts; the study defined a group of growth factors, cytokines and chemokines expressed at high to medium levels by CPC. Among them, IL-1, GROa (CXCL1), CXCL6 (GCP2) and IL-8 are examples whose expression was confirmed by most techniques used. ELISA showed that CXCL6 is significantly overexpressed in CPC conditioned medium (CM) (18- to 26-fold) and western blot confirmed expression of its receptors CXCR1 and CXCR2. Addition of anti-CXCL6 completely abolished migration in CPC-CM compared with anti-CXCR2, which promoted partial inhibition, and anti-CXCR1, which was inefficient. Anti-CXCL6 also significantly inhibited CPC CM angiogenic activity. In vivo evaluation also supported a relevant role for angiogenesis. Altogether, these results suggest a notable angiogenic potential in CPC-CM and identify CXCL6 as an important paracrine factor for CPC that signals mainly through CXCR2.
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MESH Headings
- Animals
- Antibodies, Neutralizing/pharmacology
- Cell Movement
- Chemokine CXCL1/genetics
- Chemokine CXCL1/metabolism
- Chemokine CXCL6/antagonists & inhibitors
- Chemokine CXCL6/genetics
- Chemokine CXCL6/metabolism
- Culture Media, Conditioned/chemistry
- Culture Media, Conditioned/metabolism
- Fibroblasts/cytology
- Fibroblasts/drug effects
- Fibroblasts/metabolism
- Gene Expression Regulation
- Human Umbilical Vein Endothelial Cells/cytology
- Human Umbilical Vein Endothelial Cells/drug effects
- Human Umbilical Vein Endothelial Cells/metabolism
- Humans
- Interleukin-1/genetics
- Interleukin-1/metabolism
- Interleukin-8/genetics
- Interleukin-8/metabolism
- Male
- Mesenchymal Stem Cells/cytology
- Mesenchymal Stem Cells/drug effects
- Mesenchymal Stem Cells/metabolism
- Mice
- Mice, Inbred C57BL
- Myocardium/cytology
- Myocardium/metabolism
- Neovascularization, Physiologic/genetics
- Paracrine Communication/genetics
- Proteome/genetics
- Proteome/metabolism
- Receptors, Interleukin-8A/antagonists & inhibitors
- Receptors, Interleukin-8A/genetics
- Receptors, Interleukin-8A/metabolism
- Receptors, Interleukin-8B/antagonists & inhibitors
- Receptors, Interleukin-8B/genetics
- Receptors, Interleukin-8B/metabolism
- Signal Transduction
- Stem Cells/cytology
- Stem Cells/drug effects
- Stem Cells/metabolism
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Affiliation(s)
- José Luis Torán
- Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), Campus Universidad Autónoma de Madrid, 28049, Madrid, Spain
- Cardiovascular Development and Repair Department, Spanish National Cardiovascular Research Center (CNIC), Melchor Fernández Almagro 3, 28029, Madrid, Spain
| | - Susana Aguilar
- Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), Campus Universidad Autónoma de Madrid, 28049, Madrid, Spain
- Cardiovascular Development and Repair Department, Spanish National Cardiovascular Research Center (CNIC), Melchor Fernández Almagro 3, 28029, Madrid, Spain
| | - Juan Antonio López
- Cardiovascular Proteomics Laboratory, Spanish National Cardiovascular Research Center (CNIC), Melchor Fernaández Almagro 3, 28029, Madrid, Spain
| | - Carlos Torroja
- Bioinformatics Unit, Spanish National Cardiovascular Research Center (CNIC), Melchor Fernández Almagro 3, 28029, Madrid, Spain
| | - Juan Antonio Quintana
- Cardiovascular Development and Repair Department, Spanish National Cardiovascular Research Center (CNIC), Melchor Fernández Almagro 3, 28029, Madrid, Spain
- Cell and Developmental Biology, Spanish National Cardiovascular Research Center (CNIC), Melchor Fernández Almagro 3, 28029, Madrid, Spain
| | - Cesar Santiago
- Department of Macromolecular Structures, Centro Nacional de Biotecnología (CNB-CSIC), Campus Universidad Autónoma de Madrid, 28049, Madrid, Spain
| | - José Luis Abad
- Coretherapix SLU, Santiago Grisolia 2, 28769, Tres Cantos, Madrid, Spain
| | - Patricia Gomes-Alves
- Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Av. da República, 2780-157, Oeiras, Portugal
- iBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2781-901, Oeiras, Portugal
| | - Andrés Gonzalez
- Myocardial pathophysiology, Spanish National Cardiovascular Research Center (CNIC), Melchor Fernández Almagro 3, 28029, Madrid, Spain
| | - Juan Antonio Bernal
- Myocardial pathophysiology, Spanish National Cardiovascular Research Center (CNIC), Melchor Fernández Almagro 3, 28029, Madrid, Spain
| | - Luis Jesús Jiménez-Borreguero
- Cell and Developmental Biology, Spanish National Cardiovascular Research Center (CNIC), Melchor Fernández Almagro 3, 28029, Madrid, Spain
- Hospital de la Princesa, Diego de León 62, 28006, Madrid, Spain
| | - Paula Marques Alves
- Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Av. da República, 2780-157, Oeiras, Portugal
- iBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2781-901, Oeiras, Portugal
| | - Luis R-Borlado
- Coretherapix SLU, Santiago Grisolia 2, 28769, Tres Cantos, Madrid, Spain
| | - Jesús Vázquez
- Cardiovascular Proteomics Laboratory, Spanish National Cardiovascular Research Center (CNIC), Melchor Fernaández Almagro 3, 28029, Madrid, Spain
| | - Antonio Bernad
- Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), Campus Universidad Autónoma de Madrid, 28049, Madrid, Spain.
- Cardiovascular Development and Repair Department, Spanish National Cardiovascular Research Center (CNIC), Melchor Fernández Almagro 3, 28029, Madrid, Spain.
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17
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Sex Differences of Human Cardiac Progenitor Cells in the Biological Response to TNF- α Treatment. Stem Cells Int 2017; 2017:4790563. [PMID: 29104594 PMCID: PMC5623773 DOI: 10.1155/2017/4790563] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Revised: 06/09/2017] [Accepted: 06/14/2017] [Indexed: 01/25/2023] Open
Abstract
Adult cardiac progenitor cells (CPCs), isolated as cardiosphere-derived cells (CDCs), represent promising candidates for cardiac regenerative therapy. CDCs can be expanded in vitro manyfolds without losing their differentiation potential, reaching numbers that are appropriate for clinical applications. Since mechanisms of successful CDC survival and engraftment in the damaged myocardium are still critical and unresolved issues, we aimed at deciphering possible key factors capable of bolstering CDC function. In particular, the response and the phenotype of CDCs exposed to low concentrations of the multifunctional cytokine tumor necrosis factor α (TNF-α), known to be capable of activating cell survival pathways, have been investigated. Furthermore, differential biological responses of CDCs from male and female donors, in terms of cell cycle progression and cell spreading, have also been assessed. The results obtained indicate that (i) the intracellular signaling activated in our experimental conditions is most likely due to the prosurvival and proliferative signaling of TNF-α receptor 2 and that (ii) cells from female patients appear more responsive to TNF-α treatment in terms of cell cycle progression and migration ability. In conclusion, the present report highlights the hypothesis that TNF-stimulated CDCs isolated from females may represent a promising candidate for cardiac regenerative therapy applications.
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18
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Wang Y, Liu C, Wang J, Zhang Y, Chen L. Iodine-131 induces apoptosis in human cardiac muscle cells through the p53/Bax/caspase-3 and PIDD/caspase-2/ t‑BID/cytochrome c/caspase-3 signaling pathway. Oncol Rep 2017; 38:1579-1586. [PMID: 28714021 DOI: 10.3892/or.2017.5813] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Accepted: 06/27/2017] [Indexed: 11/06/2022] Open
Abstract
The aim of this study was to elucidate the effects of iodine-131 on the induction of apoptosis in human cardiac muscle cells and the underlying molecular mechanisms. We found that iodine-131 reduced cell proliferation, induced apoptosis, induced p53, PIDD, t-BID (mitochondria) protein expression, suppressed cytochrome c (mitochondria) protein expression, and increased Bax protein expression, and promoted caspase-2, -3 and -9 expression levels in human cardiac muscle cells. Meanwhile, si-p53 inhibited the effects of iodine-131 on the reduction in cell proliferation and induction of apoptosis in human cardiac muscle cells through regulation of Bax/cytochrome c/caspase-3 and PIDD/caspase‑2/t-BID/cytochrome c/caspase-3 signaling pathway. After si-Bax reduced the effects of iodine-131, it reduced cell proliferation and induced apoptosis in human cardiac muscle cells through the cytochrome c/caspase-3 signaling pathway. However, si-caspase-2 also reduced the effects of iodine-131 on the reduction of cell proliferation and induction of apoptosis in human cardiac muscle cells through the t-BID/cytochrome c/caspase-3 signaling pathway. These findings demonstrated that iodine-131 induces apoptosis in human cardiac muscle cells through the p53/Bax/caspase-3 and PIDD/caspase-2/t-BID/cytochrome c/caspase-3 signaling pathway.
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Affiliation(s)
- Yansheng Wang
- Department of Nuclear Medicine, Central Hospital of Cangzhou, Cangzhou, Hebei 061001, P.R. China
| | - Changqing Liu
- Department of Nuclear Medicine, People's Hospital of Weifang, Weifang, Shandong 261041, P.R. China
| | - Jianchun Wang
- Department of Nuclear Medicine, Central Hospital of Cangzhou, Cangzhou, Hebei 061001, P.R. China
| | - Yang Zhang
- Department of Nuclear Medicine, Central Hospital of Cangzhou, Cangzhou, Hebei 061001, P.R. China
| | - Linlin Chen
- Department of Anesthesiology, Central Hospital of Cangzhou, Cangzhou, Hebei 061001, P.R. China
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19
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Li H, Ding C, Ding ZL, Ling M, Wang T, Wang W, Huang B. 17β-Oestradiol promotes differentiation of human embryonic stem cells into dopamine neurons via cross-talk between insulin-like growth factors-1 and oestrogen receptor β. J Cell Mol Med 2017; 21:1605-1618. [PMID: 28244646 PMCID: PMC5542902 DOI: 10.1111/jcmm.13090] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Accepted: 12/13/2016] [Indexed: 12/17/2022] Open
Abstract
Human embryonic stem cells (hESCs) can self‐renew and differentiate into all cell lineages. E2 is known to exhibit positive effects on embryo development. Although the importance of E2 in many physiological processes has been reported, to date few researchers have investigated the effects of E2 on hESCs differentiation. We studied the effects of E2 on dopamine (DA) neuron induction of hESCs and its related signalling pathways using the three‐stage protocol. In our study, 0.1 μM E2 were applied to hESCs‐derived human embryoid bodies (hEBs) and effects of E2 on neural cells differentiation were investigated. Protein and mRNA level assay indicated that E2 up‐regulated the expression of insulin‐like growth factors (IGF)‐1, ectoderm, neural precursor cells (NPC) and DA neuron markers, respectively. The population of hESC‐derived NPCs and DA neurons was increased to 92% and 93% to that of DMSO group, respectively. Furthermore, yield of DA neuron‐secreted tyrosine hydroxylase (TH) and dopamine was also increased. E2‐caused promotion was relieved in single inhibitor (ICI or JB1) group partly, and E2 effects were repressed more stronger in inhibitors combination (ICI plus JB1) group than in single inhibitor group at hEBs, hNPCs and hDA neurons stages. Owing to oestrogen receptors regulate multiple brain functions, when single or two inhibitors were used to treat neural differentiation stage, we found that oestrogen receptor (ER)β but not ERα is strongly repressed at the hNPCs and hDA neurons stage. These findings, for the first time, demonstrate the molecular cascade and related cell biology events involved in E2‐improved hNPC and hDA neuron differentiation through cross‐talk between IGF‐1 and ERβ in vitro.
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Affiliation(s)
- Hong Li
- Center of Reproduction and Genetics, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou, China
| | - Chenyue Ding
- Center of Reproduction and Genetics, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou, China
| | - Zhi-Liang Ding
- Department of Neurosurgery, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou, China
| | - Mingfa Ling
- Center of Reproduction and Genetics, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou, China
| | - Ting Wang
- Center of Reproduction and Genetics, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou, China
| | - Wei Wang
- Center of Reproduction and Genetics, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou, China
| | - Boxian Huang
- Center of Reproduction and Genetics, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou, China
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20
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Maric-Bilkan C, Arnold AP, Taylor DA, Dwinell M, Howlett SE, Wenger N, Reckelhoff JF, Sandberg K, Churchill G, Levin E, Lundberg MS. Report of the National Heart, Lung, and Blood Institute Working Group on Sex Differences Research in Cardiovascular Disease: Scientific Questions and Challenges. Hypertension 2016; 67:802-7. [PMID: 26975706 DOI: 10.1161/hypertensionaha.115.06967] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Christine Maric-Bilkan
- From the Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (C.M.-B., M.S.L.); Department of Integrative Biology and Physiology, University of California at Los Angeles (A.P.A.); Department of Regenerative Medicine, Texas Heart Institute, Houston (D.A.T.); Department of Physiology, Medical College of Wisconsin, Milwaukee (M.D.); Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada (S.E.H.); Cardiovascular Physiology, University of Manchester, Manchester, United Kingdom (S.E.H.); Department of Medicine, Emory University School of Medicine, Atlanta, GA (N.W.); Department of Physiology, University of Mississippi Medical Center, Jackson (J.F.R.); Department of Medicine, Georgetown University Medical Center, Washington, DC (K.S.); The Jackson Laboratory, Bar Harbor, ME (G.C.); and Department of Endocrinology, Diabetes, and Metabolism, University of California, Irvine (E.L.).
| | - Arthur P Arnold
- From the Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (C.M.-B., M.S.L.); Department of Integrative Biology and Physiology, University of California at Los Angeles (A.P.A.); Department of Regenerative Medicine, Texas Heart Institute, Houston (D.A.T.); Department of Physiology, Medical College of Wisconsin, Milwaukee (M.D.); Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada (S.E.H.); Cardiovascular Physiology, University of Manchester, Manchester, United Kingdom (S.E.H.); Department of Medicine, Emory University School of Medicine, Atlanta, GA (N.W.); Department of Physiology, University of Mississippi Medical Center, Jackson (J.F.R.); Department of Medicine, Georgetown University Medical Center, Washington, DC (K.S.); The Jackson Laboratory, Bar Harbor, ME (G.C.); and Department of Endocrinology, Diabetes, and Metabolism, University of California, Irvine (E.L.)
| | - Doris A Taylor
- From the Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (C.M.-B., M.S.L.); Department of Integrative Biology and Physiology, University of California at Los Angeles (A.P.A.); Department of Regenerative Medicine, Texas Heart Institute, Houston (D.A.T.); Department of Physiology, Medical College of Wisconsin, Milwaukee (M.D.); Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada (S.E.H.); Cardiovascular Physiology, University of Manchester, Manchester, United Kingdom (S.E.H.); Department of Medicine, Emory University School of Medicine, Atlanta, GA (N.W.); Department of Physiology, University of Mississippi Medical Center, Jackson (J.F.R.); Department of Medicine, Georgetown University Medical Center, Washington, DC (K.S.); The Jackson Laboratory, Bar Harbor, ME (G.C.); and Department of Endocrinology, Diabetes, and Metabolism, University of California, Irvine (E.L.)
| | - Melinda Dwinell
- From the Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (C.M.-B., M.S.L.); Department of Integrative Biology and Physiology, University of California at Los Angeles (A.P.A.); Department of Regenerative Medicine, Texas Heart Institute, Houston (D.A.T.); Department of Physiology, Medical College of Wisconsin, Milwaukee (M.D.); Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada (S.E.H.); Cardiovascular Physiology, University of Manchester, Manchester, United Kingdom (S.E.H.); Department of Medicine, Emory University School of Medicine, Atlanta, GA (N.W.); Department of Physiology, University of Mississippi Medical Center, Jackson (J.F.R.); Department of Medicine, Georgetown University Medical Center, Washington, DC (K.S.); The Jackson Laboratory, Bar Harbor, ME (G.C.); and Department of Endocrinology, Diabetes, and Metabolism, University of California, Irvine (E.L.)
| | - Susan E Howlett
- From the Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (C.M.-B., M.S.L.); Department of Integrative Biology and Physiology, University of California at Los Angeles (A.P.A.); Department of Regenerative Medicine, Texas Heart Institute, Houston (D.A.T.); Department of Physiology, Medical College of Wisconsin, Milwaukee (M.D.); Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada (S.E.H.); Cardiovascular Physiology, University of Manchester, Manchester, United Kingdom (S.E.H.); Department of Medicine, Emory University School of Medicine, Atlanta, GA (N.W.); Department of Physiology, University of Mississippi Medical Center, Jackson (J.F.R.); Department of Medicine, Georgetown University Medical Center, Washington, DC (K.S.); The Jackson Laboratory, Bar Harbor, ME (G.C.); and Department of Endocrinology, Diabetes, and Metabolism, University of California, Irvine (E.L.)
| | - Nanette Wenger
- From the Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (C.M.-B., M.S.L.); Department of Integrative Biology and Physiology, University of California at Los Angeles (A.P.A.); Department of Regenerative Medicine, Texas Heart Institute, Houston (D.A.T.); Department of Physiology, Medical College of Wisconsin, Milwaukee (M.D.); Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada (S.E.H.); Cardiovascular Physiology, University of Manchester, Manchester, United Kingdom (S.E.H.); Department of Medicine, Emory University School of Medicine, Atlanta, GA (N.W.); Department of Physiology, University of Mississippi Medical Center, Jackson (J.F.R.); Department of Medicine, Georgetown University Medical Center, Washington, DC (K.S.); The Jackson Laboratory, Bar Harbor, ME (G.C.); and Department of Endocrinology, Diabetes, and Metabolism, University of California, Irvine (E.L.)
| | - Jane F Reckelhoff
- From the Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (C.M.-B., M.S.L.); Department of Integrative Biology and Physiology, University of California at Los Angeles (A.P.A.); Department of Regenerative Medicine, Texas Heart Institute, Houston (D.A.T.); Department of Physiology, Medical College of Wisconsin, Milwaukee (M.D.); Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada (S.E.H.); Cardiovascular Physiology, University of Manchester, Manchester, United Kingdom (S.E.H.); Department of Medicine, Emory University School of Medicine, Atlanta, GA (N.W.); Department of Physiology, University of Mississippi Medical Center, Jackson (J.F.R.); Department of Medicine, Georgetown University Medical Center, Washington, DC (K.S.); The Jackson Laboratory, Bar Harbor, ME (G.C.); and Department of Endocrinology, Diabetes, and Metabolism, University of California, Irvine (E.L.)
| | - Kathryn Sandberg
- From the Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (C.M.-B., M.S.L.); Department of Integrative Biology and Physiology, University of California at Los Angeles (A.P.A.); Department of Regenerative Medicine, Texas Heart Institute, Houston (D.A.T.); Department of Physiology, Medical College of Wisconsin, Milwaukee (M.D.); Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada (S.E.H.); Cardiovascular Physiology, University of Manchester, Manchester, United Kingdom (S.E.H.); Department of Medicine, Emory University School of Medicine, Atlanta, GA (N.W.); Department of Physiology, University of Mississippi Medical Center, Jackson (J.F.R.); Department of Medicine, Georgetown University Medical Center, Washington, DC (K.S.); The Jackson Laboratory, Bar Harbor, ME (G.C.); and Department of Endocrinology, Diabetes, and Metabolism, University of California, Irvine (E.L.)
| | - Gary Churchill
- From the Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (C.M.-B., M.S.L.); Department of Integrative Biology and Physiology, University of California at Los Angeles (A.P.A.); Department of Regenerative Medicine, Texas Heart Institute, Houston (D.A.T.); Department of Physiology, Medical College of Wisconsin, Milwaukee (M.D.); Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada (S.E.H.); Cardiovascular Physiology, University of Manchester, Manchester, United Kingdom (S.E.H.); Department of Medicine, Emory University School of Medicine, Atlanta, GA (N.W.); Department of Physiology, University of Mississippi Medical Center, Jackson (J.F.R.); Department of Medicine, Georgetown University Medical Center, Washington, DC (K.S.); The Jackson Laboratory, Bar Harbor, ME (G.C.); and Department of Endocrinology, Diabetes, and Metabolism, University of California, Irvine (E.L.)
| | - Ellis Levin
- From the Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (C.M.-B., M.S.L.); Department of Integrative Biology and Physiology, University of California at Los Angeles (A.P.A.); Department of Regenerative Medicine, Texas Heart Institute, Houston (D.A.T.); Department of Physiology, Medical College of Wisconsin, Milwaukee (M.D.); Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada (S.E.H.); Cardiovascular Physiology, University of Manchester, Manchester, United Kingdom (S.E.H.); Department of Medicine, Emory University School of Medicine, Atlanta, GA (N.W.); Department of Physiology, University of Mississippi Medical Center, Jackson (J.F.R.); Department of Medicine, Georgetown University Medical Center, Washington, DC (K.S.); The Jackson Laboratory, Bar Harbor, ME (G.C.); and Department of Endocrinology, Diabetes, and Metabolism, University of California, Irvine (E.L.)
| | - Martha S Lundberg
- From the Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (C.M.-B., M.S.L.); Department of Integrative Biology and Physiology, University of California at Los Angeles (A.P.A.); Department of Regenerative Medicine, Texas Heart Institute, Houston (D.A.T.); Department of Physiology, Medical College of Wisconsin, Milwaukee (M.D.); Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada (S.E.H.); Cardiovascular Physiology, University of Manchester, Manchester, United Kingdom (S.E.H.); Department of Medicine, Emory University School of Medicine, Atlanta, GA (N.W.); Department of Physiology, University of Mississippi Medical Center, Jackson (J.F.R.); Department of Medicine, Georgetown University Medical Center, Washington, DC (K.S.); The Jackson Laboratory, Bar Harbor, ME (G.C.); and Department of Endocrinology, Diabetes, and Metabolism, University of California, Irvine (E.L.).
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Harnessing the secretome of cardiac stem cells as therapy for ischemic heart disease. Biochem Pharmacol 2016; 113:1-11. [PMID: 26903387 DOI: 10.1016/j.bcp.2016.02.012] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Accepted: 02/18/2016] [Indexed: 12/22/2022]
Abstract
Adult stem cells continue to promise opportunities to repair damaged cardiac tissue. However, precisely how adult stem cells accomplish cardiac repair, especially after ischemic damage, remains controversial. It has been postulated that the clinical benefit of adult stem cells for cardiovascular disease results from the release of cytokines and growth factors by the transplanted cells. Studies in animal models of myocardial infarction have reported that such paracrine factors released from transplanted adult stem cells contribute to improved cardiac function by several processes. These include promoting neovascularization of damaged tissue, reducing inflammation, reducing fibrosis and scar formation, as well as protecting cardiomyocytes from apoptosis. In addition, these factors might also stimulate endogenous repair by activating cardiac stem cells. Interestingly, stem cells discovered to be resident in the heart appear to be functionally superior to extra-cardiac adult stem cells when transplanted for cardiac repair and regeneration. In this review, we discuss the therapeutic potential of cardiac stem cells and how the proteins secreted from these cells might be harnessed to promote repair and regeneration of damaged cardiac tissue. We also highlight how recent controversies about the efficacy of adult stem cells in clinical trials of ischemic heart disease have not dampened enthusiasm for the application of cardiac stem cells and their paracrine factors for cardiac repair: the latter have proved superior to the mesenchymal stem cells used in most clinical trials in the past, some of which appear to have been conducted with sub-optimal rigor.
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Sivasinprasasn S, Shinlapawittayatorn K, Chattipakorn SC, Chattipakorn N. Estrogenic Impact on Cardiac Ischemic/Reperfusion Injury. J Cardiovasc Transl Res 2016; 9:23-39. [PMID: 26786980 DOI: 10.1007/s12265-016-9675-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Accepted: 01/07/2016] [Indexed: 11/29/2022]
Abstract
The increase in cardiovascular disease and metabolic syndrome incidence following the onset of menopause has highlighted the role of estrogen as a cardiometabolic protective agent. Specifically regarding the heart, estrogen induced an improvement in cardiac function, preserved calcium homeostasis, and inhibited the mitochondrial apoptotic pathway. The beneficial effects of estrogen in relation to cardiac ischemia/reperfusion (I/R) injury, such as reduced infarction and ameliorated post-ischemic recovery, have also been shown. Nevertheless, controversial findings exist and estrogen therapy is reported to be related to a higher rate of thromboembolic events and atrial fibrillation in post-menopausal women. Therefore, greater clarification is needed to evaluate the exact potential of estrogen use in cases of cardiac I/R injury. This article reviews the effects of estrogen, in both acute and chronic treatment, and collates the studies with regard to their in vivo, in vitro, or clinical trial settings in cases of cardiac I/R injury and myocardial infarction.
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Affiliation(s)
- Sivaporn Sivasinprasasn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.,Cardiac Electrophysiology unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,School of Medicine, Mae Fah Luang University, Chiang Rai, Thailand.,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
| | - Krekwit Shinlapawittayatorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.,Cardiac Electrophysiology unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
| | - Siriporn C Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.,Department of Oral Biology and Diagnostic Science, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand.,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
| | - Nipon Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand. .,Cardiac Electrophysiology unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. .,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand.
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Luo T, Kim JK. The Role of Estrogen and Estrogen Receptors on Cardiomyocytes: An Overview. Can J Cardiol 2015; 32:1017-25. [PMID: 26860777 DOI: 10.1016/j.cjca.2015.10.021] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Revised: 10/27/2015] [Accepted: 10/27/2015] [Indexed: 01/07/2023] Open
Abstract
Sex differences in the onset and manifestation of cardiovascular diseases are well known, yet the mechanism behind this discrepancy remains obscure. Estrogen and its corresponding receptors have been studied for their positive salutary effects in women for decades. Estrogen protects the heart from various forms of stress, including cytotoxic, ischemic, and hypertrophic stimuli. The postulated underlying mechanism is complex, and involves the actions of the hormone on the endothelium and myocardium. Although the effects of estrogen on the coronary endothelium are well-described, delineation of the hormone's action on cardiomyocytes is still evolving. The focus of this article is to review the accumulated literature and latest data on the role of estrogen and its receptors on cardiomyocytes, the contractile cellular units of the myocardium.
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Affiliation(s)
- Tao Luo
- University of California Irvine, School of Medicine, Irvine, California, USA
| | - Jin Kyung Kim
- University of California Irvine, School of Medicine, Irvine, California, USA.
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