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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 β-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-PGF2α (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
Robert T. Eberhardt, Marc A. Forgione, Andre Cap, Jane A. Leopold, M. Audrey Rudd, Maria Trolliet, Stanley Heydrick, Rachel Stark, Elizabeth S. Klings, Nicanor I. Moldovan, Mohammed Yaghoubi, Pascal J. Goldschmidt-Clermont, Harrison W. Farber, Richard Cohen, Joseph Loscalzo
Does Deffective CBS in Endothelial Cells Account for Hyperhomocysteinemia Induced Dysfunction?
Submitter: Xing Li Wang | xwang@darwin.sfbr.org
Southwest Foundation Foundation for Biomedical Research
Published September 7, 2000
Eberhardt and colleagues have elegantly demonstrated direct effects of mild hyperhomocysteinemia on both oxidative stress and endothelial dysfunction in vivo. They have done so in mice heterozygous for a deletion in the cystathionine beta-synthase (CBS) gene. This is so far the closest in vivo model simulating the true human mild hyperhomocysteinemia and illustrated convincingly the causal relationship. Since plasma homocysteine levels are twofold higher in the CBS-/+ mice, they propose that the detrimental vascular effects are mediated by the elevated circulating homocysteine levels. However, several questions remain. Firstly, CBS -/+ mice should obviously also have a defective CBS gene in their endothelial cells, which would then affect the methionine/homocysteine metabolism within endothelial cells. Is it possible that the effect authors observed on endothelial dysfunction is mediated directly by the enzymatic deficiency within endothelial cells rather than by elevated circulating homocysteine levels? One of the key points distinguishing this study from previous in vivo or in vitro models is that nearly none of the previous models have the defective enzymes in the target endothelial cells. Could this be one of the possible reasons to explain the differences in endothelial responses to vasodilators between this study and the others? Another potential complication in evaluating the model is that we lack detailed comparisons in methionine/homocysteine metabolic pathways between mice and human.
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