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Endothelial dysfunction in a murine model of mild hyperhomocyst(e)inemia
R T Eberhardt1, M A Forgione, A Cap
1Evans Department of Medicine, Whitaker Cardiovascular Institute, and. Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
The Journal of Clinical Investigation
|August 23, 2000
Summary
Mild hyperhomocysteinemia impairs blood vessel function by reducing nitric oxide activity. This study in mice shows increased oxidative stress contributes to endothelial dysfunction, a risk factor for atherosclerosis.
Area of Science:
- Cardiovascular Science
- Biochemistry
- Pathophysiology
Background:
- Homocysteine is a known risk factor for atherosclerosis and thrombotic events.
- Endothelial dysfunction is a critical early step in the development of cardiovascular disease.
Purpose of the Study:
- To investigate the role of reactive oxygen species and nitric oxide bioactivity loss in endothelial dysfunction in mild hyperhomocysteinemia.
- To explore the impact of reduced cystathionine beta-synthase (CBS) gene expression on vascular function.
Main Methods:
- Utilized a mouse model heterozygous for a CBS gene deletion (CBS(-/+) mice).
- Assessed endothelial function using isolated aortic rings and in situ mesenteric arterioles.
- Measured oxidative stress markers, including 8-epi-PGF(2alpha) and 3-nitrotyrosine, and superoxide production.
Main Results:
- CBS(-/+) mice exhibited impaired acetylcholine-induced aortic relaxation and paradoxical vasoconstriction in mesenteric microvessels.
- Nitric oxide-mediated vasodilation (sodium nitroprusside) remained intact.
- Increased superoxide production and 3-nitrotyrosine staining were observed in aortic tissue, indicating heightened oxidative stress.
Conclusions:
- Mild hyperhomocysteinemia, resulting from reduced CBS expression, leads to impaired endothelium-dependent vasodilation.
- Oxidative stress contributes to the inactivation of nitric oxide, promoting endothelial dysfunction in chronic mild hyperhomocysteinemia.
- Endothelial dysfunction occurs early in this model, preceding structural arterial changes.
