Diabetic HDL-associated myristic acid inhibits acetylcholine-induced nitric oxide generation by preventing the association of endothelial nitric oxide synthase with calmodulin

Abstract

Smart EJ. Diabetic HDL-associated myristic acid inhibits acetylcholineinduced nitric oxide generation by preventing the association of endothelial nitric oxide synthase with calmodulin. Am J Physiol Cell Physiol 294: C295-C305, 2008. First published October 31, 2007 doi:10.1152/ajpcell.00042.2007.-In the current study, we examined whether diabetes affected the ability of HDL to stimulate nitric oxide (NO) production. Using HDL isolated from both diabetic humans and diabetic mouse models, we found that female HDL no longer induced NO synthesis, despite containing equivalent amounts of estrogen as nondiabetic controls. Furthermore, HDL isolated from diabetic females and males prevented acetylcholine-induced stimulation of NO generation. Analyses of both the human and mouse diabetic HDL particles showed that the HDLs contained increased levels of myristic acid. To determine whether myristic acid associated with HDL particles was responsible for the decrease in NO generation, myristic acid was added to HDL isolated from nondiabetic humans and mice. Myristic acid-associated HDL inhibited the generation of NO in a dose-dependent manner. Importantly, diabetic HDL did not alter the levels of endothelial NO synthase or acetylcholine receptors associated with the cells. Surprisingly, diabetic HDL inhibited ionomycin-induced stimulation of NO production without affecting ionomycin-induced increases in intracellular calcium. Further analysis indicated that diabetic HDL prevented calmodulin from interacting with endothelial NO synthase (eNOS) but did not affect the activation of calmodulin kinase or calcium-independent mechanisms for stimulating eNOS. These studies are the first to show that a specific fatty acid associated with HDL inhibits the stimulation of NO generation. These findings have important implications regarding cardiovascular disease in diabetic patients. fatty acid; lipoprotein; diabetes; signaling CARDIOVASCULAR DISEASES are influenced by both genetic and environmental factors that can negatively or positively influence the development and progression of cardiovascular diseases, such as plasma levels of LDL and HDL (25,26). High plasma levels of LDL promote the accumulation of cholesterol in vessel wall macrophages and the formation of atherosclerotic plaque (3,

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Acide myristique : nouvelles fonctions de régulation et de signalisation

“…Cependant, cette activation n'est plus retrouvée chez les patientes diabétiques. Or, comparées aux HDL témoins, la seule différence significative des HDL isolées chez les diabétiques est leur composition, puisqu'elles contiennent 3 à 4 fois plus d'acide myristique [33]. Des HDL issues de patients sains supplémentés en C14:0 ont un effet inhibiteur identique sur l'activité eNOS 3 n-3).…”

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