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on February 24, 2005

Arteriosclerosis, Thrombosis, and Vascular Biology. 2005
Published online before print February 24, 2005, doi: 10.1161/01.ATV.0000160549.60980.a8
A more recent version of this article appeared on May 1, 2005
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Submitted on September 22, 2004
Accepted on February 11, 2005

Free Fatty Acid Impairment of Nitric Oxide Production in Endothelial Cells Is Mediated by IKK{beta}

Francis Kim *; Kelly A. Tysseling ; Julie Rice ; Matilda Pham ; Lutfiyah Haji ; Byron M. Gallis ; Arnold S. Baas ; Pathmaja Paramsothy ; Cecilia M. Giachelli ; Marshall A. Corson ; and Elaine W. Raines

From the Department of Medicine (F.K., K.A.T., M.P., L.H., B.M.G., A.S.B., P.P., M.A.C.), Division of Cardiology, University of Washington, Harborview Medical Center, Seattle, Wash; the Department of Bioengineering (J.R., C.M.G.), University of Washington; and the Department of Pathology (E.W.R.), University of Washington.

* To whom correspondence should be addressed. E-mail: fkim{at}u.washington.edu.

Objective--Free fatty acids (FFA) are commonly elevated in diabetes and obesity and have been shown to impair nitric oxide (NO) production by endothelial cells. However, the signaling pathways responsible for FFA impairment of NO production in endothelial cells have not been characterized. Insulin receptor substrate-1 (IRS-1) regulation is critical for activation of endothelial nitric oxide synthase (eNOS) in response to stimulation by insulin or fluid shear stress.

Methods and Results--We demonstrate that insulin-mediated tyrosine phosphorylation of IRS-1 and serine phosphorylation of Akt, eNOS, and NO production are significantly inhibited by treatment of bovine aortic endothelial cells with 100 µmol/L FFA composed of palmitic acid for 3 hours before stimulation with 100 nM insulin. This FFA preparation also increases, in a dose-dependent manner, IKK{beta} activity, which regulates activation of NF- {kappa}B, a transcriptional factor associated with inflammation. Similarly, elevation of other common FFA such as oleic and linoleic acid also induce IKK{beta} activation and inhibit insulin-mediated eNOS activation.

Conclusions--Overexpression of a kinase inactive form of IKK{beta} blocks the ability of FFA to inhibit insulin-dependent NO production, whereas overexpression of wild-type IKK{beta} recapitulates the effect of FFA on insulin-dependent NO production. Elevated levels of common FFA found in human serum activate IKK{beta} in endothelial cells leading to reduced NO production, and thus may serve to link pathways involved in inflammation and endothelial dysfunction.
Key words: diabetes • endothelial dysfunction • endothelial nitric oxide synthase • free fatty acids • IKK{beta} • nitric oxide


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