Oleic Acid Inhibits Endothelial Nitric Oxide Synthase by a Protein Kinase C–Independent Mechanism

Abstract

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)

Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation.

“…We found, however, that serum cholesterol and blood pressure elevations could account for only a small proportion of the endothelial dysfunction displayed in these subjects (4). A recent report by Davda et al (5) has suggested that the FFA oleic acid reduces the activity of the endothelial nitric oxide synthase in vitro. Given that insulin resistance in man is characterized by elevated circulating levels of FFAs (6, 7) it is not unreasonable to suspect that FFAs may play a role in the endothelial dysfunction displayed by insulin-resistant patients.…”

Effects of age, gender and metabolic factors on endothelium‐dependent vasodilation: a population‐based study

“…It cannot be concluded from the present investigation which of the metabolic derangements associated with abdominal obesity is responsible for the attenuation in EDV. In the experimental setting, FFAs, especially oleic acid and linoleic acid, have been shown to impair EDV [32]. Also, small dense LDL, involved in the generation of oxidized LDL, could attenuate EDV possibly through oxygen free radical formation [33], whilst HDL cholesterol has been shown to improve EDV [34].…”

Non-esterified fatty acids and blood pressure elevation: a mechanism for hypertension in subjects with obesity/insulin resistance?

“…In contrast, the endothelium-independent vasodilatating action of sodium nitroprusside was not altered, a finding indicating that NEFAs were only interfering with endotheliumdependent vasodilatation. 36 In addition to the above findings, elegant in vivo experiments provided detailed information for the effects of NEFAs on endothelial function in humans. Steinberg et al 23 observed that intra-arterial infusion of metacholine in femoral artery of lean healthy individuals during intravenous normal saline infusion resulted in an increase of leg blood flow up to about 300% in relation to baseline levels.…”

“…Both oleic and linoleic acids were reported to cause dose-dependent reduction of endothelial NO synthase (NOS) activity in bovine pulmonary artery endothelial cells. 36 In another study, addition of NEFAs in endothelial cells in culture was associated with dose-dependent reductions of NO production. This reduction was also attributed to a decrease in NOS activity, as NOS concentration in endothelial cells remained unaltered.…”