Resveratrol activates endogenous cardiac stem cells and improves myocardial regeneration following acute myocardial infarction

Stem cell antigen-l-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 1X10(6) CSCs into the peri-ischemic area (n=8/group). Mice received intragastric administration of PBS or resveratrol (2.5 mg/kg circle d) for 4 weeks after cell transplantation. Echocardiography was used to evaluate cardiac function 4 weeks after cell transplantation. Capillary densitS, and cardiomyocyte apoptosis in the peri-ischemic myocardium were assessed by cluster of differentiation 31 immunofluorescent staining and terminal deoxynucleotidyl transferase-mediateddUTP 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 -derivedfactor (SDF)-lain 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, 281.0224.08/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-la 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-la 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-la 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-la.