title: Resveratrol activates endogenous cardiac stem cells and improves myocardial regeneration following acute myocardial infarction.
abstract: Stem cell antigen-1-positive (Sca-1+) cardiac stem cells (CSCs) therapy for myocardial regeneration following acute myocardial infarction (AMI) is limited by insufficient cell viability and a high rate of apoptosis, due to the poor regional microenvironment. Resveratrol, which is a compound extracted from red wine, has been reported to protect myocardial tissue post‑AMI by increasing the expression of angiogenic and chemotactic factors. The present study aimed to investigate the effects of resveratrol on Sca‑1+ CSCs, and to optimize Sca‑1+ CSCs therapy for myocardial regeneration post‑AMI. C57/BL6 mice (age, 6 weeks) were divided into two groups, which received intragastric administration of PBS or 2.5 mg/kg.d resveratrol. The endogenous expression of Sca‑1+ CSCs in the heart was assessed on day 7. Furthermore, C57/BL6 mice underwent left anterior descending coronary artery ligation for the construction of an AMI model, and received an injection of 1x106 CSCs into the peri‑ischemic area (n=8/group). Mice received intragastric administration of PBS or resveratrol (2.5 mg/kg.d) for 4 weeks after cell transplantation. Echocardiography was used to evaluate cardiac function 4 weeks after cell transplantation. Capillary density and cardiomyocyte apoptosis in the peri‑ischemic myocardium were assessed by cluster of differentiation 31 immunofluorescent staining and terminal deoxynucleotidyl transferase‑mediated dUTP nick end labeling assay, respectively. Western blot analysis was conducted to detect the protein expression levels of vascular endothelial growth factor (VEGF) and stromal cell‑derived factor (SDF)‑1α in the myocardium. Treatment with resveratrol increased the number of endogenous Sca‑1+ CSCs in heart tissue after 7 days (PBS vs. Res, 1.85±0.41/field vs. 3.14±0.26/field, P<0.05). Furthermore, intragastric administration of resveratrol significantly increased left ventricle (LV) function 4 weeks after AMI, as determined by an increase in LV fractional shortening (CSCs vs. Res + CSCs, 28.82±1.58% vs. 31.18±2.02%, P<0.05), reduced LV end‑diastolic diameter (CSCs vs. Res + CSCs, 0.37±0.01 mm vs. 0.35±0.02 mm, P<0.05), and reduced LV end‑systolic diameter (CSCs vs. Res + CSCs, 0.26±0.01 mm vs. 0.23±0.02 mm, P<0.05). These protective effects were predominantly achieved via an increase in capillary density (CSCs vs. Res + CSCs, 281.02±24.08/field vs. 329.75±36.69/field, P<0.05) and a reduction in cardiomyocyte apoptosis (CSCs vs. Res + CSCs, 1.5±0.54/field vs. 0.83±0.40/field, P<0.05) in peri‑ischemic myocardium. Western blot analysis indicated that VEGF and SDF‑1α were upregulated in resveratrol‑treated myocardium after a 7 day treatment or 4 weeks after AMI (7 days VEGF PBS vs. Res, 0.89±0.07 vs. 1.21±0.02, P<0.05; SDF‑1α PBS vs. Res, 0.66±0.04 vs. 1.33±0.04, P<0.05; 4 weeks VEGF CSCs vs. Res + CSCs, 0.54±0.03 vs. 0.93±0.13, P<0.05; SDF‑1α CSCs vs. Res + CSCs, 0.53±0.03 vs. 0.93±0.03, P<0.05). Resveratrol activated endogenous CSCs, increased capillary density and decreased cardiomyocyte apoptosis in the peri‑ischemic myocardium, and augmented the effects of CSCs transplantation. These effects may be caused by the upregulation of VEGF and SDF‑1α.
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China.
authors.forename: Lin
authors.initials: L
authors.lastname: Ling
authors.affiliation: Department of Nephrology, The Third People's Hospital of Kunshan, Wuxi, Jiangsu 214000, P.R. China.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Gu
authors.affiliation: Department of Cardiology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu 214000, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cheng
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D054377:Chemokine CXCL12 / Q000378:metabolism; D004195:Disease Models, Animal; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D032386:Myoblasts, Cardiac / Q000187:drug effects* / Q000378:metabolism; D009203:Myocardial Infarction / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D012038:Regeneration / Q000187:drug effects*; D000077185:Resveratrol; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000950:Antigens, Ly; D015415:Biomarkers; D054377:Chemokine CXCL12; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D013267:Stilbenes; D042461:Vascular Endothelial Growth Factor A; D000077185:Resveratrol