Davda R K, Stepniakowski K T, Lu G, Ullian M E, Goodfriend T L, Egan B M
Division of Nephrology, Medical University of South Carolina, Charleston 29425-2251, USA.
Hypertension. 1995 Nov;26(5):764-70. doi: 10.1161/01.hyp.26.5.764.
Many obese hypertensive individuals have a cluster of cardiovascular risk factors. This cluster includes plasma nonesterified fatty acid concentrations and turnover rates that are higher and more resistant to suppression by insulin than in lean and obese normotensive individuals. The higher fatty acids may contribute to cardiovascular risk in these patients by inhibiting endothelial cell nitric oxide synthase activity. To test this hypothesis, we quantified the effects of oleic (18:1[cis]) and other 18-carbon fatty acids on nitric oxide synthase activity in cultured bovine pulmonary artery endothelial cells by measuring the conversion of [3H]L-arginine to [3H]L-citrulline. Oleic acid (from 10 to 100 mumol/L) caused a concentration-dependent decrease in nitric oxide synthase activity at baseline and during ATP and ionomycin (Ca2+ ionophore) stimulation. At 100 mumol/L, linoleic (18:2[cis]) and oleic acids caused similar reductions of nitric oxide synthase activity, whereas elaidic (18:1[trans]) and stearic (18:0) acids had no effect. Oleic acid also inhibited the endothelium-dependent vasodilator response to acetylcholine in rabbit femoral artery rings preconstricted with phenylephrine (P < .05) but had no effect on the response to nitroprusside. The pattern of 18-carbon fatty acid effects on nitric oxide synthase activity in endothelial cells is consistent with activation of protein kinase C. Although oleic acid increased protein kinase C activity in endothelial cells, neither depletion of protein kinase C by 24-hour pretreatment with phorbol 12-myristate 13-acetate nor its inhibition with staurosporine eliminated the inhibitory effect of oleic acid on nitric oxide synthase.(ABSTRACT TRUNCATED AT 250 WORDS)
许多肥胖的高血压患者存在一系列心血管危险因素。这一系列危险因素包括血浆非酯化脂肪酸浓度及转换率，与瘦的和肥胖的血压正常者相比，这些患者的血浆非酯化脂肪酸浓度更高，且对胰岛素抑制作用的抵抗性更强。较高的脂肪酸水平可能通过抑制内皮细胞一氧化氮合酶活性，增加这些患者发生心血管疾病的风险。为验证这一假设，我们通过测量[3H]L-精氨酸向[3H]L-瓜氨酸的转化，定量研究了油酸（18:1[顺式]）和其他18碳脂肪酸对培养的牛肺动脉内皮细胞一氧化氮合酶活性的影响。油酸（浓度为10至100μmol/L）在基线水平以及ATP和离子霉素（钙离子载体）刺激期间，均可导致一氧化氮合酶活性呈浓度依赖性降低。在100μmol/L时，亚油酸（18:2[顺式]）和油酸可使一氧化氮合酶活性产生相似程度的降低，而反油酸（18:1[反式]）和硬脂酸（18:0）则无此作用。油酸还可抑制苯肾上腺素预收缩的兔股动脉环对乙酰胆碱的内皮依赖性血管舒张反应（P <.05），但对硝普钠的反应无影响。18碳脂肪酸对内皮细胞一氧化氮合酶活性的影响模式与蛋白激酶C的激活一致。尽管油酸可增加内皮细胞中的蛋白激酶C活性，但用佛波酯12-肉豆蔻酸酯13-乙酸酯进行24小时预处理耗尽蛋白激酶C，或用星形孢菌素抑制蛋白激酶C，均不能消除油酸对一氧化氮合酶的抑制作用。（摘要截选至250词）
