title: Strategic targets to induce neovascularization by resveratrol in hypercholesterolemic rat myocardium: role of caveolin-1, endothelial nitric oxide synthase, hemeoxygenase-1, and vascular endothelial growth factor.
abstract: Endothelial dysfunction and impaired angiogenesis constitute a hallmark of hypercholesterolemia. This study was designed to examine the effects of resveratrol, an antioxidant with lipid-lowering properties similar to those of statins, on neovascularization along with caveolar interaction with proangiogenic molecules in hypercholesterolemic rats. Animals were divided into: rats maintained on a normal diet (control group); rats maintained on a 5% high-cholesterol diet for 8 weeks (HC group); and rats maintained on a 5% high-cholesterol diet for 8 weeks and administered resveratrol (20 mg/kg) orally for 2 weeks (HCR group). Myocardial infarction was induced by ligating the left anterior descending artery. Herein we examined a novel method for stimulating myocardial angiogenesis by pharmacological preconditioning with resveratrol at both the capillary and arteriolar levels and the potential role of hemeoxygenase-1, endothelial nitric oxide synthase and caveolin-1 in mediating such a response. We also investigated the functional relevance of such treatment by assessing whether the induced neovascularization can help preserve left ventricle-contractile functional reserve in the setting of a chronic hypercholesterolemic condition. Four weeks after sham surgery and left anterior descending artery occlusion, rats underwent echocardiographic evaluation, which revealed improvement in ejection fraction and fractional shortening in the HCR group compared with the HC group. Left ventricular tissue sections displayed increased capillary and arteriolar density in the HCR group compared with the HC group. Western blot analysis revealed downregulation of vascular endothelial growth factor and hemeoxygenase-1 and increased association of caveolin-1 eNOS in the HC group, decreasing the availability of eNOS to the system; which was reversed with resveratrol treatment in the HCR group. This study was further validated in cardiac-specific hemeoxygenase-1-overexpressed mice assuming molecular cross-talk between the targets. Hence, our data identified potential regulators that primarily attenuate endothelial dysfunction by resveratrol therapy in hypercholesterolemic myocardium.
authors.affiliation: Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut Health Center, Farmington, CT, USA.
authors.forename: Suresh Varma
authors.initials: SV
authors.lastname: Penumathsa
authors.forename: Srikanth
authors.initials: S
authors.lastname: Koneru
authors.forename: Samson Mathews
authors.initials: SM
authors.lastname: Samuel
authors.forename: Gautam
authors.initials: G
authors.lastname: Maulik
authors.forename: Debasis
authors.initials: D
authors.lastname: Bagchi
authors.forename: Shaw-Fang
authors.initials: SF
authors.lastname: Yet
authors.forename: Venogopal P
authors.initials: VP
authors.lastname: Menon
authors.forename: Nilanjana
authors.initials: N
authors.lastname: Maulik
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D015153:Blotting, Western; D051242:Caveolin 1 / Q000187:drug effects / Q000378:metabolism; D003326:Coronary Circulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D051547:Heme Oxygenase-1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000378:metabolism
chemical_list: D000975:Antioxidants; D051242:Caveolin 1; D013267:Stilbenes; D042461:Vascular Endothelial Growth Factor A; D052250:Nitric Oxide Synthase Type III; D051547:Heme Oxygenase-1; D000077185:Resveratrol