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Protective vascular and cardiac effects of inducible nitric oxide synthase in mice with hyperhomocysteinemia
Journal article   Open access   Peer reviewed

Protective vascular and cardiac effects of inducible nitric oxide synthase in mice with hyperhomocysteinemia

Sanjana Dayal, Ilya O Blokhin, Rochelle A Erger, Melissa Jensen, Erland Arning, Jeff W Stevens, Teodoro Bottiglieri, Frank M Faraci and Steven R Lentz
PloS one, Vol.9(9), pp.e107734-e107734
2014
DOI: 10.1371/journal.pone.0107734
PMCID: PMC4167199
PMID: 25226386
url
https://doi.org/10.1371/journal.pone.0107734View
Published (Version of record) Open Access

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.
 Methionine - blood Reactive Oxygen Species - metabolism Hyperhomocysteinemia - metabolism Endothelium, Vascular - drug effects Male Cerebral Arteries - drug effects Myocardial Reperfusion Injury - pathology Myocardium - metabolism Female Myocardial Reperfusion Injury - genetics Disease Models, Animal Vasodilator Agents - pharmacology Nitric Oxide Synthase Type II - deficiency Endothelium, Vascular - physiopathology Homocysteine - blood Mice, Knockout Myocardial Reperfusion Injury - metabolism Phenotype Thrombosis - metabolism Animals Diet Nitric Oxide Synthase Type II - genetics Cerebral Arteries - metabolism Endothelium, Vascular - metabolism Hyperhomocysteinemia - genetics Mice Nitric Oxide Synthase Type II - metabolism

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