Background-Endothelium-derived nitric oxide (NO) is produced by an oxidative reaction catalyzed by endothelial NO synthase (eNOS). NO plays a crucial role in controlling cell growth and apoptosis, as well as having well-characterized vasodilator and antithrombotic actions. More recently, endothelium-derived NO was shown to be involved in postdevelopmental vascular remodeling and angiogenesis, as well as in the formation of limb vasculature during embryogenesis. Therefore, we investigated the role of endothelium-derived NO during cardiovascular development using mice deficient in eNOS. Methods and Results-We examined the hearts of 12 mature eNOS-deficient and 26 mature wild-type mice. Five of the mature eNOS-deficient mice had a bicuspid aortic valve; none of the 26 wild-type animals exhibited identifiable valvular or cardiac abnormalities. Immunohistochemical analysis revealed prominent eNOS expression localized to the endothelium lining the valve cusps of the aorta in mature wild-type mice; expression was localized to the myocardium and endothelial cell monolayer lining the valve leaflets in the developing embryo. Conclusions-These results show a strong association between eNOS deficiency and the presence of a bicuspid aortic valve; they provide the first molecular insight into one of the most common types of congenital cardiac abnormality. Key Words: nitric oxide Ⅲ endothelium Ⅲ mice, knockout Ⅲ heart defects, congenital Ⅲ valves N itric oxide (NO) is a free radical gas that is synthesized from L-arginine in a complex oxidative reaction catalyzed by 3 distinct isoforms of NO synthase: endothelial (eNOS), inducible (iNOS), and neuronal (nNOS). 1 The neuronal isoform is highly expressed in neuronal cells and skeletal muscle, whereas the endothelial isoform is predominantly expressed in endothelial cells and produces small amounts of NO in response to intimal shear stress or agonists such as bradykinin. 2,3 The inducible isoform is expressed in many cell types, including macrophages and smooth muscle cells, primarily in response to inflammatory cytokines. Once expressed, this isoform can produce large amounts of NO in a continuous manner. 1,2 Endothelium-derived NO is crucial in the regulation of cell growth and apoptosis; it also has a well-characterized role as a vasodilator and antithrombotic agent. 1 More recently, NO derived from the endothelium was shown to be involved in postdevelopmental vascular remodeling and angiogenesis, as well as in the formation of limb vasculature during embryogenesis. 4 -6 The valve leaflets of the heart originate from mesenchymal outgrowths known as cardiac cushions. Cushion formation is localized to the atrioventricular canal and ventricular outflow tract regions of the primary heart tube. These formations arise from regional thickenings of the cardiac jelly, the extracellular matrix that resides between the myocardium and endocardium of the primitive heart tube. This event involves the transformation of a subset of endothelial cells of the endocardium into mesenchyme. The mo...

Background-Homeless people represent an extremely disadvantaged group in North America. Among older homeless men, cardiovascular disease (CVD) is the leading cause of death. The objective of this study was to examine cardiovascular risk factors in a representative sample of homeless adults and identify opportunities for improved risk factor modification. Methods and Results-Homeless persons were randomly selected at shelters for single adults in Toronto. Response rate was 79%. Participants (nϭ202) underwent interviews, physical measurements, and blood sampling. The mean age of participants was 42 years, and 89% were men. The prevalence of smoking among homeless subjects (78%; 95% confidence interval [CI], 72% to 84%) was significantly higher than in the general population (standardized morbidity ratio [SMR], 254; 95% CI, 216 to 297). Hypertension, high cholesterol, and diabetes were not more prevalent than in the general population but were often poorly controlled. Homeless men were significantly less likely to be overweight or obese than men in the general population (SMR, 79; 95% CI, 63 to 98). Cocaine use in the last year was reported by 29% of subjects (95% CI, 23% to 36%). CVD was reported by 15% of subjects, fewer than one third of whom reported taking aspirin or cholesterol-lowering medication. According to multiple-risk-factor equations, the median estimated 10-year absolute risk of myocardial infarction or coronary death among homeless men aged 30 to 74 years was 5% (interquartile range, 3% to 9%). Conclusions-Cardiovascular

We conclude that a nonselective ET receptor antagonist substantially inhibited the development of atherosclerosis in a genetic model of hyperlipidemia, possibly by inhibiting macrophage foam-cell formation, suggesting a role for these agents in the treatment and prevention of atherosclerotic vascular disease.

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