RESUMEN

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.

Asunto(s)

Endotelio Vascular/fisiopatología , Hiperhomocisteinemia/fisiopatología , Acetilcolina/farmacología , Animales , Aorta/efectos de los fármacos , Aorta/patología , Aorta/fisiopatología , Arteriosclerosis/etiología , Cistationina betasintasa/genética , Cistationina betasintasa/metabolismo , Dinoprost/análogos & derivados , Dinoprost/metabolismo , Modelos Animales de Enfermedad , F2-Isoprostanos , Heterocigoto , Humanos , Hiperhomocisteinemia/genética , Hiperhomocisteinemia/patología , Técnicas In Vitro , Peróxidos Lipídicos/metabolismo , Ratones , Ratones Mutantes , Nitroprusiato/farmacología , Especies Reactivas de Oxígeno/metabolismo , Factores de Riesgo , Trombosis/etiología , Tirosina/análogos & derivados , Tirosina/metabolismo , Vasodilatación/efectos de los fármacos

RESUMEN

Endothelial dysfunction is an early and persistent vascular abnormality in the evolution of atherothrombotic disease. Risk factors for atherosclerosis promote an inflammatory oxidative environment in the vasculature that induces pathologic changes in endothelial function, including the support of enhanced smooth muscle tone, thrombosis, and smooth muscle proliferation. This article provides an overview of the molecular basis of endothelial dysfunction and of its diagnosis and treatment.

Asunto(s)

Enfermedad Coronaria/fisiopatología , Vasos Coronarios/fisiopatología , Endotelio Vascular/fisiopatología , Antioxidantes/uso terapéutico , Enfermedad Coronaria/prevención & control , Terapia de Reemplazo de Estrógeno , Femenino , Humanos , Peroxidación de Lípido , Persona de Mediana Edad , Estrés Oxidativo , Factores de Riesgo

RESUMEN

The endothelial dysfunction associated with nitric oxide (NO) depletion accompanies the development of atherothrombotic disease. Recent evidence suggests that oxidative reactions in the vasculature promote atherothrombosis. Several risk factors for atherothrombosis, such as diabetes mellitus, cigarette smoking, hypertension, hyperhomocyst(e)inemia and hypercholesterolemia, are associated with oxidative reactions in the vasculature and with endothelial dysfunction. Traditional and novel treatments for atherothrombosis increase bioavailable NO and may decrease oxidant stress; however, the effect of this treatment on improving the long-term prognosis of patients with risk factors for atherothrombosis has yet to be determined.