title: Protective vascular and cardiac effects of inducible nitric oxide synthase in mice with hyperhomocysteinemia.
abstract: Diet-induced hyperhomocysteinemia produces endothelial and cardiac dysfunction and promotes thrombosis through a mechanism proposed to involve oxidative stress. Inducible nitric oxide synthase (iNOS) is upregulated in hyperhomocysteinemia and can generate superoxide. We therefore tested the hypothesis that iNOS mediates the adverse oxidative, vascular, thrombotic, and cardiac effects of hyperhomocysteinemia. Mice deficient in iNOS (Nos2-/-) and their wild-type (Nos2+/+) littermates were fed a high methionine/low folate (HM/LF) diet to induce mild hyperhomocysteinemia, with a 2-fold increase in plasma total homocysteine (P<0.001 vs. control diet). Hyperhomocysteinemic Nos2+/+ mice exhibited endothelial dysfunction in cerebral arterioles, with impaired dilatation to acetylcholine but not nitroprusside, and enhanced susceptibility to carotid artery thrombosis, with shortened times to occlusion following photochemical injury (P<0.05 vs. control diet). Nos2-/- mice had decreased rather than increased dilatation responses to acetylcholine (P<0.05 vs. Nos2+/+ mice). Nos2-/- mice fed control diet also exhibited shortened times to thrombotic occlusion (P<0.05 vs. Nos2+/+ mice), and iNOS deficiency failed to protect from endothelial dysfunction or accelerated thrombosis in mice with hyperhomocysteinemia. Deficiency of iNOS did not alter myocardial infarct size in mice fed the control diet but significantly increased infarct size and cardiac superoxide production in mice fed the HM/LF diet (P<0.05 vs. Nos2+/+ mice). These findings suggest that endogenous iNOS protects from, rather than exacerbates, endothelial dysfunction, thrombosis, and hyperhomocysteinemia-associated myocardial ischemia-reperfusion injury. In the setting of mild hyperhomocysteinemia, iNOS functions to blunt cardiac oxidative stress rather than functioning as a source of superoxide.
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America.
authors.forename: Sanjana
authors.initials: S
authors.lastname: Dayal
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America; Interdisciplinary Graduate Program in Molecular and Cellular Biology, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America.
authors.forename: Ilya O
authors.initials: IO
authors.lastname: Blokhin
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America; Veterans Affairs Medical Center, Iowa City, Iowa, United States of America.
authors.forename: Rochelle A
authors.initials: RA
authors.lastname: Erger
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America.
authors.forename: Melissa
authors.initials: M
authors.lastname: Jensen
authors.affiliation: Baylor Institute of Metabolic Disease, Dallas, Texas, United States of America.
authors.forename: Erland
authors.initials: E
authors.lastname: Arning
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America.
authors.forename: Jeff W
authors.initials: JW
authors.lastname: Stevens
authors.affiliation: Baylor Institute of Metabolic Disease, Dallas, Texas, United States of America.
authors.forename: Teodoro
authors.initials: T
authors.lastname: Bottiglieri
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America; Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America; Francois M. Abboud Cardiovascular Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America.
authors.forename: Frank M
authors.initials: FM
authors.lastname: Faraci
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Lentz
mesh_terms: D000818:Animals; D002536:Cerebral Arteries / Q000187:drug effects / Q000378:metabolism; D004032:Diet; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D006710:Homocysteine / Q000097:blood; D020138:Hyperhomocysteinemia / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008715:Methionine / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D013927:Thrombosis / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D006710:Homocysteine; D008715:Methionine; D052247:Nitric Oxide Synthase Type II