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.