The role of fatty acid on endothelial nitric oxide synthase activation and atherogenesis.

摘要

Dietary fatty acids have various effects on endothelial function and cardiovascular disease. The goal of current study was to determine effects of free fatty acids on endothelial nitric oxide synthase (eNOS) activation and their further effects on blood pressure and atherogenesis.; Using human microvascular endothelial cells which endogenously express both eNOS and CD36, we tested the effects of free fatty acids on eNOS activation. Surprisingly, only myristic acid, and to a lesser extent palmitic acid, stimulated eNOS. The stimulation of eNOS was dose- and time-dependent. Experiments with a CD36 blocking antibody demonstrated that the effect of myristic acid on eNOS required CD36. Further mechanistic studies demonstrated that myristic acid stimulated eNOS was independent of PI-3-kinase, Akt kinase, and calcium, but was dependent on the activation of AMP kinase. These data demonstrate an unexpected link between myristic acid, CD36, AMP kinase, and eNOS activity.; We next designed diets and experiments to investigate the effects of fatty acids on blood pressure and atherogenesis. Our results showed that myristic acid did not decrease blood pressure in C57BL6 wild type mice. We used the LDL receptor knock out mice to investigate the role of fatty acids on atherogenesis. Surprisingly, myristic acid caused a 6 fold increase in lesion formation compared with the control diet, without causing significant changes in weight gain, plasma total cholesterol, triglyceride compared with control diet. To determine the role of NO in the generation of atherosclerosis by myristic acid, LDLR-/- mice were fed with high myristic acid diet along with L-NAME, a NOS inhibitor. Our results demonstrated that L-NAME treatment decreased lesion formation by 50% in myristic acid diet fed mice, without any significant changes in plasma total cholesterol and triglyceride levels. In addition, L-NAME treatment also decreased protein nitration and LOOH in plasma of mice fed with high myristic acid diet. Taken together, these data suggest NO derived peroxynitrite may be responsible for the increased atherogenesis level with the myristic acid diet fed mice.