doi: 10.1161/hq1201.100456
© 2002 American Heart Association, Inc.
Vascular Biology |
Cellular Redox State and Endothelial Dysfunction in Mildly Hyperhomocysteinemic Cystathionine ß-Synthase–Deficient Mice
From the Whitaker Cardiovascular Institute, Evans Department of Medicine (N.W., S.H., Y.-Y.Z., J.L.), and the Departments of Pharmacology (C.B.) and Pathology (A.C.), Boston University School of Medicine, Boston, Mass. N.W. is currently at the Medizinische Poliklinik Innenstadt, Ludwig-Maximilians-Universität, Munich, Germany.
Correspondence to Dr Joseph Loscalzo, Boston University School of Medicine, 715 Albany St W507, Boston, MA 02118-2394. E-mail jloscalz{at}bu.edu
Previous in vitro experiments have shown that hyperhomocysteinemia leads to oxidative inactivation of nitric oxide, in part by inhibiting the expression of cellular glutathione peroxidase (GPx-1). To elucidate the role of intracellular redox status on homocysteine-induced endothelial dysfunction and oxidant stress, heterozygous cystathionine ß-synthase–deficient (CBS-/+) and wild-type (CBS+/+) mice were treated with the cysteine donor L-2-oxothiazolidine-4-carboxylic acid (OTC). CBS-/+ mice had significantly lower GPx-1 activity compared with their CBS+/+ littermates, and OTC treatment led to a modest increase in tissue GPx-1 activity and significant increases in total thiols and in reduced glutathione levels in both CBS+/+ and CBS-/+ mice. Superfusion of the mesentery with ß-methacholine or bradykinin produced dose-dependent vasodilation of mesenteric arterioles in CBS+/+ mice and in CBS+/+ mice treated with OTC. In contrast, mesenteric arterioles from CBS-/+ mice manifested dose-dependent vasoconstriction in response to both agonists. OTC treatment of CBS-/+ mice restored normal microvascular vasodilator reactivity to ß-methacholine and bradykinin. These findings demonstrate that mild hyperhomocysteinemia leads to endothelial dysfunction in association with decreased bioavailable nitric oxide. Increasing the cellular thiol and reduced glutathione pools and increasing GPx-1 activity restores endothelial function. These findings emphasize the importance of intracellular redox balance for nitric oxide bioactivity and endothelial function.
Key Words: homocysteine • endothelial function • oxidant stress • nitric oxide • P-selectin
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