(Hypertension. 1995;26:764.)
© 1995 American Heart Association, Inc.
Articles |
Oleic Acid Inhibits Endothelial Nitric Oxide Synthase by a Protein Kinase C–Independent Mechanism
From the Division of Nephrology (R.K.D., M.E.U.) and Clinical Pharmacology (K.T.S., G.L., B.M.E.), Departments of Medicine and Pharmacology, Medical University of South Carolina, Charleston, and Departments of Medicine and Pharmacology (T.L.G.), University of Wisconsin and William S. Middleton Memorial Veterans Hospital, Madison.
Correspondence to Brent M. Egan, MD, Division of Clinical Pharmacology, Medical University of South Carolina, 171 Ashley Ave, CSB 826H, Charleston, SC 29425-2251.
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 µmol/L) caused a concentration-dependent decrease in nitric oxide synthase activity at baseline and during ATP and ionomycin (Ca2+ ionophore) stimulation. At 100 µmol/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. The vascular ring studies further indicate that oleic acid reduces the response to acetylcholine by inhibiting nitric oxide synthase activity rather than reducing the activation of guanylate cyclase or the effects of cGMP. Thus, elevated oleic acid values in obese hypertensive individuals may contribute to impaired endothelium-dependent vasodilation by a protein kinase C–independent mechanism.
Key Words: fatty acids, nonesterified • nitric oxide • endothelium, vascular • endothelium-derived relaxing factor • hypertension, obesity
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