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(Circulation Research. 2006;98:768.)
© 2006 American Heart Association, Inc.

Molecular Medicine

Role of Endothelial Nitric Oxide Synthase in the Regulation of SREBP Activation by Oxidized Phospholipids

Nima M. Gharavi, Nancy A. Baker, Kevin P. Mouillesseaux, Winnie Yeung, Henry M. Honda, Xavier Hsieh, Michael Yeh, Eric J. Smart, Judith A. Berliner

From the Division of Cardiology, Department of Medicine (N.M.G., K.P.M., W.Y., H.M.H., X.H., M.Y., J.A.B.); Department of Pathology (N.M.G., N.A.B., M.Y., J.A.B.); and Department of Physiological Science (N.A.B.), University of California, Los Angeles; and Department of Pediatrics (E.J.S.), University of Kentucky, Lexington.

Correspondence to Nima M. Gharavi, 13-239 CHS-Pathology, 650 Charles E. Young Dr S, Los Angeles, CA 90095. E-mail ngharavi{at}ucla.edu

Oxidized-1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (Ox-PAPC), found in atherosclerotic lesions and other sites of chronic inflammation, activates endothelial cells (EC) to synthesize chemotactic factors, such as interleukin (IL)-8. Previously, we demonstrated that the sustained induction of IL-8 transcription by Ox-PAPC was mediated through the activation of sterol regulatory element–binding protein (SREBP). We now present evidence for the role of endothelial nitric oxide synthase (eNOS) in the activation of SREBP by Ox-PAPC. Ox-PAPC treatment of EC induced a dose- and time-dependent activation of eNOS, as measured by phosphorylation of serine 1177, dephosphorylation of threonine 495, and the conversion of L-arginine to L-citrulline. Activation of eNOS by Ox-PAPC was regulated through a phosphatidylinositol-3-kinase/Akt-mediated mechanism. These studies also demonstrated that pretreatment of EC with NOS inhibitor, N-nitro-L-arginine-methyl ester (L-NAME), significantly inhibited Ox-PAPC–induced IL-8 synthesis. Because SREBP activation had been previously shown to regulate IL-8 transcription by Ox-PAPC, we examined the effects of L-NAME on Ox-PAPC–induced SREBP activation. Our data demonstrated that Ox-PAPC–induced SREBP activation and expression of SREBP target genes were significantly reduced by pretreatment with L-NAME. Interestingly, treatment of EC with NO donor, S-nitroso-N-acetylpenicillamine, did not activate SREBP, suggesting that NO alone was not sufficient for SREBP activation. Rather, our findings indicated that superoxide (O₂^·–), in combination with NO, regulated SREBP activation by Ox-PAPC. We found that Ox-PAPC treatment generated O₂^·– through an eNOS-mediated mechanism and that mercaptoethylguanidine, a peroxynitrite scavenger, reduced SREBP activation by Ox-PAPC. Taken together, these findings propose a novel role for eNOS in the activation of SREBP and SREBP-mediated inflammatory processes.

Key Words: oxidized phospholipids • interleukin-8 • endothelium • nitric oxide • cholesterol

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