title: Role of homocysteinylation of ACE in endothelial dysfunction of arteries.
abstract: The direct impact of de novo synthesis of homocysteine (Hcy) and its reactive metabolites, Hcy-S-S-Hcy and Hcy thiolactone (HCTL), on vascular function has not been fully elucidated. We hypothesized that Hcy synthesized within endothelial cells affects activity of angiotensin-converting enzyme (ACE) by direct homocysteinylation of its amino- and/or sulfhydryl moieties. This covalent modification enhances ACE reactivity toward angiotensin II (ANG II)-NADPH oxidase-superoxide-dependent endothelial dysfunction. Mesenteric and coronary arteries isolated from normal rats were incubated for 3 days with or without exogenous methionine (Met, 0.1-0.3 mM), a precursor to Hcy. Incubation of arteries in Met-free media resulted in time-dependent decreases in vascular Hcy formation. By contrast, vessels incubated with Met produced Hcy in a dose-dependent manner. There was a notably greater de novo synthesis of Hcy from endothelial than from smooth muscle cells. Enhanced levels of Hcy production significantly impaired shear stress-induced dilation and release of nitric oxide, events that are associated with elevated production of vascular superoxide. Each of these processes was attenuated by ANG II type I receptor blocker or ACE and NADPH oxidase inhibitors. In addition, in vitro exposure of purified ACE to Hcy-S-S-Hcy/HCTL resulted in formation of homocysteinylated ACE and an enhanced ACE activity. The enhanced ACE activity was confirmed in isolated coronary and mesenteric arteries that had been exposed directly to Hcy-S-S-Hcy/HCTL or after Met incubation. In conclusion, vasculature-derived Hcy initiates endothelial dysfunction that, in part, may be mediated by ANG II-dependent activation of NADPH oxidase in association with homocysteinylation of ACE.
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, New York; and.
authors.forename: An
authors.initials: A
authors.lastname: Huang
authors.affiliation: Department of Biochemistry, New York Medical College, Valhalla, New York.
authors.forename: John T
authors.initials: JT
authors.lastname: Pinto
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, New York; and.
authors.forename: Ghezal
authors.initials: G
authors.lastname: Froogh
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, New York; and.
authors.forename: Sharath
authors.initials: S
authors.lastname: Kandhi
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, New York; and.
authors.forename: Jun
authors.initials: J
authors.lastname: Qin
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, New York; and.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wolin
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, New York; and.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Hintze
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, New York; and dong_sun@nymc.edu.
authors.forename: Dong
authors.initials: D
authors.lastname: Sun
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D003331:Coronary Vessels / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D006710:Homocysteine / Q000096:biosynthesis / Q000378:metabolism*; D008297:Male; D008638:Mesenteric Arteries / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D008715:Methionine / Q000494:pharmacology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D006710:Homocysteine; D013481:Superoxides; D009569:Nitric Oxide; D008715:Methionine; D019255:NADPH Oxidases; D007703:Peptidyl-Dipeptidase A
keywords: angiotensin-converting enzyme; endothelium; homocysteine; homocysteinylation; superoxide