Resveratrol enhances neovascularization in the infarcted rat myocardium through the induction of thioredoxin-1, heme oxygenase-1 and vascular endothelial growth factor.
We have previously shown that resveratrol possesses cardioprotective effect, which may be attributed to its ability to (i) stimulate nitric oxide production and (ii) free radical scavenging activity. Since resveratrol is one of the major components of certain varieties of red grapes, these events may underlie the cardioprotective effects thought to be obtained from moderate red wine consumption. Here we report resveratrol enhanced myocardial angiogenesis both in vivo and in vitro by induction of vascular endothelial growth factor (VEGF), which was regulated by thioredoxin-1 (Trx-1) and heme oxygenase-1 (HO-1). Human coronary arteriolar endothelial cells exposed to resveratrol or Trx-1 on Matrigel demonstrated significantly accelerated tubular morphogenesis with induction of HO-1 and VEGF expression. This angiogenic response was repressed by tin-protoporphyrin IX (SnPP), an HO-1 inhibitor, along with downregulation of VEGF expression. However Trx-1 expression was not affected by SnPP. Again, rat neonatal cardiomyocytes treated with resveratrol significantly expressed Trx-1, HO-1 as well as VEGF. Rats were orally administered with resveratrol (1 mg/kg per day) for 14 days and then underwent permanent left anterior descending coronary artery (LAD) occlusion to document similar pro-angiogenic effect. Our results demonstrated that pretreatment with resveratrol markedly reduced infarct size 24 h after myocardial infarction (MI) and increased capillary density in the peri-infarct myocardium along with better left ventricular function 4 days after MI compared with vehicle-treated control. Concomitantly, resveratrol-treated myocardium after MI significantly induced Trx-1, HO-1 and VEGF expression. This effect was blocked by SnPP. Our findings suggest that resveratrol mediates cardioprotection and neovascularization through Trx-1-HO-1-VEGF pathway in rat ischemic myocardium.
Kaga
Shigeaki
S
Molecular Cardiology Laboratory, Department of Surgery, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-1110, USA.
Zhan
Lijun
L
Matsumoto
Masahiko
M
Maulik
Nilanjana
N
D000818:Animals; D003094:Collagen; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects; D004338:Drug Combinations; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007797:Laminin; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D009203:Myocardial Infarction / Q000188:drug therapy*; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009929:Organ Size; D011509:Proteoglycans; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology* / Q000627:therapeutic use; D013879:Thioredoxins / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D004338:Drug Combinations; D007797:Laminin; D008665:Metalloporphyrins; D011509:Proteoglycans; D011524:Protoporphyrins; D013267:Stilbenes; C495697:Txn1 protein, rat; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D013879:Thioredoxins; D003094:Collagen; C032628:tin protoporphyrin IX; D051547:Heme Oxygenase-1; D000077185:Resveratrol