title: Endothelial dysfunction in a murine model of mild hyperhomocyst(e)inemia.
abstract: Homocysteine is a risk factor for the development of atherosclerosis and its thrombotic complications. We have employed an animal model to explore the hypothesis that an increase in reactive oxygen species and a subsequent loss of nitric oxide bioactivity contribute to endothelial dysfunction in mild hyperhomocysteinemia. We examined endothelial function and in vivo oxidant burden in mice heterozygous for a deletion in the cystathionine beta-synthase (CBS) gene, by studying isolated, precontracted aortic rings and mesenteric arterioles in situ. CBS(-/+) mice demonstrated impaired acetylcholine-induced aortic relaxation and a paradoxical vasoconstriction of mesenteric microvessels in response to superfusion of methacholine and bradykinin. Cyclic GMP accumulation following acetylcholine treatment was also impaired in isolated aortic segments from CBS(-/+) mice, but aortic relaxation and mesenteric arteriolar dilation in response to sodium nitroprusside were similar to wild-type. Plasma levels of 8-epi-PGF(2alpha) (8-IP) were somewhat increased in CBS(-/+) mice, but liver levels of 8-IP and phospholipid hydroperoxides, another marker of oxidative stress, were normal. Aortic tissue from CBS(-/+) mice also demonstrated greater superoxide production and greater immunostaining for 3-nitrotyrosine, particularly on the endothelial surface. Importantly, endothelial dysfunction appears early in CBS(-/+) mice in the absence of structural arterial abnormalities. Hence, mild hyperhomocysteinemia due to reduced CBS expression impairs endothelium-dependent vasodilation, likely due to impaired nitric oxide bioactivity, and increased oxidative stress apparently contributes to inactivating nitric oxide in chronic, mild hyperhomocysteinemia.
authors.affiliation: Evans Department of Medicine, Whitaker Cardiovascular Institute, and. Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: R T
authors.initials: RT
authors.lastname: Eberhardt
authors.forename: M A
authors.initials: MA
authors.lastname: Forgione
authors.forename: A
authors.initials: A
authors.lastname: Cap
authors.forename: J A
authors.initials: JA
authors.lastname: Leopold
authors.forename: M A
authors.initials: MA
authors.lastname: Rudd
authors.forename: M
authors.initials: M
authors.lastname: Trolliet
authors.forename: S
authors.initials: S
authors.lastname: Heydrick
authors.forename: R
authors.initials: R
authors.lastname: Stark
authors.forename: E S
authors.initials: ES
authors.lastname: Klings
authors.forename: N I
authors.initials: NI
authors.lastname: Moldovan
authors.forename: M
authors.initials: M
authors.lastname: Yaghoubi
authors.forename: P J
authors.initials: PJ
authors.lastname: Goldschmidt-Clermont
authors.forename: H W
authors.initials: HW
authors.lastname: Farber
authors.forename: R
authors.initials: R
authors.lastname: Cohen
authors.forename: J
authors.initials: J
authors.lastname: Loscalzo
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D001161:Arteriosclerosis / Q000209:etiology; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000378:metabolism; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000503:physiopathology*; D028441:F2-Isoprostanes; D006579:Heterozygote; D006801:Humans; D020138:Hyperhomocysteinemia / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D066298:In Vitro Techniques; D008054:Lipid Peroxides / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009599:Nitroprusside / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012307:Risk Factors; D013927:Thrombosis / Q000209:etiology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
chemical_list: D028441:F2-Isoprostanes; D008054:Lipid Peroxides; D017382:Reactive Oxygen Species; D009599:Nitroprusside; C075750:8-epi-prostaglandin F2alpha; C002744:3-nitrotyrosine; D014443:Tyrosine; D015237:Dinoprost; D003541:Cystathionine beta-Synthase; D000109:Acetylcholine