title: Resveratrol inhibits neointimal formation after arterial injury through an endothelial nitric oxide synthase-dependent mechanism.
abstract: Revascularization procedures used for treatment of atherosclerosis often result in restenosis. Resveratrol (RSV), an antioxidant with cardiovascular benefits, decreases neointimal formation after arterial injury by a mechanism that is still not fully clarified. Our main objective was to address the role of nitric oxide synthases (NOSes) and more specifically the endothelial-NOS (eNOS) isoform as a mediator of this effect. RSV (4 mg/kg/day, s.c.) alone or in combination with the NOS inhibitor N-nitro-L-arginine methyl ester (L-NAME) (2 mg/kg/day, s.c.) was given to Sprague-Dawley rats beginning at 3 days before arterial (carotid or aortic) injury. RSV reduced neointimal formation by 50% (P<0.01), decreased intimal cell proliferation by 37% (P<0.01) and reduced inflammatory markers such as PECAM and MMP-9 mRNA. These effects of RSV were all abolished by coadministration of l-NAME. Oral RSV (beginning at 5 days before arterial injury) reduced neointimal thickness after femoral wire injury in mice, however this effect was not observed in eNOS knockout mice. This is the first report of RSV decreasing neointimal cell proliferation and neointimal growth through an eNOS-dependent mechanism.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, M5S 1A8 Canada.
authors.forename: Danna M
authors.initials: DM
authors.lastname: Breen
authors.forename: Vernon W
authors.initials: VW
authors.lastname: Dolinsky
authors.forename: Hangjun
authors.initials: H
authors.lastname: Zhang
authors.forename: Husam
authors.initials: H
authors.lastname: Ghanim
authors.forename: June
authors.initials: J
authors.lastname: Guo
authors.forename: Margaret
authors.initials: M
authors.lastname: Mroziewicz
authors.forename: Evangelia L
authors.initials: EL
authors.lastname: Tsiani
authors.forename: Michelle P
authors.initials: MP
authors.lastname: Bendeck
authors.forename: Paresh
authors.initials: P
authors.lastname: Dandona
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
authors.forename: Scott P
authors.initials: SP
authors.lastname: Heximer
authors.forename: Adria
authors.initials: A
authors.lastname: Giacca
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology / Q000293:injuries / Q000473:pathology; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002339:Carotid Arteries / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D020212:Carotid Artery Injuries / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005263:Femoral Artery / Q000187:drug effects* / Q000201:enzymology / Q000293:injuries / Q000473:pathology; D005786:Gene Expression Regulation; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D058426:Neointima; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D013267:Stilbenes / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D057772:Vascular System Injuries / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology
chemical_list: D002317:Cardiovascular Agents; D004791:Enzyme Inhibitors; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D013267:Stilbenes; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C496316:Nos3 protein, rat; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat; D000077185:Resveratrol; D019331:NG-Nitroarginine Methyl Ester