Published online before print September 23, 2004, doi: 10.1161/01.RES.0000146030.53089.18
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Submitted on May 27, 2004
Revised on September 10, 2004
Accepted on September 14, 2004
Role for Sterol Regulatory Element-Binding Protein in Activation of Endothelial Cells by Phospholipid Oxidation Products
Michael Yeh ;
From the Departments of Medicine (M.Y., A.L.C., J.C., A.N.D., D.K.V., P.G., J.A.B.) and Pathology (M.Y., A.L.C., D.T., J-H.Q., M.C.F., T.H., K.M., J.A.B.), David Geffen School of Medicine at University of California Los Angeles; Bristol-Myers Squibb, Pharmaceutical Research Institute (W-P.Y., T.K.), Princeton, NJ; Division of Biomedical Sciences (Y.L., J.Y-J.S.), University of California, Riverside.
* To whom correspondence should be addressed. E-mail: jberliner{at}mednet.ucla.edu.
Oxidized phospholipids, including oxidation products of palmitoyl-arachidonyl-phosphatidyl choline (PAPC), are mediators of inflammation in endothelial cells (ECs) and known to induce several chemokines, including interleukin-8 (IL-8). In this study, we show that oxidized PAPC (OxPAPC), which accumulates in atherosclerotic lesions, paradoxically depletes endothelial cholesterol, causing caveolin-1 internalization from the plasma membrane to the endoplasmic reticulum and Golgi, and activates sterol regulatory element-binding protein (SREBP). Cholesterol loading reversed these effects. SREBP activation resulted in increased transcription of the low-density lipoprotein receptor, a target gene of SREBP. We also provide evidence that cholesterol depletion and SREBP activation are signals for OxPAPC induction of IL-8. Cholesterol depletion by methyl-
-cyclodextrin induced IL-8 synthesis in a dose-dependent manner. Furthermore, cholesterol loading of ECs by either the cholesterol-cyclodextrin complex or caveolin-1 overexpression inhibited OxPAPC induction of IL-8. These observations suggest that changes in cholesterol level can modulate IL-8 synthesis in ECs. The OxPAPC induction of IL-8 was mediated through the increased binding of SREBP to the IL-8 promoter region, as revealed by mobility shift assays. Overexpression of either dominant-negative SREBP cleavage-activating protein or 25-hydroxycholesterol significantly suppressed the effect of OxPAPC on IL-8 transcription. A role for SREBP activation in atherosclerosis is suggested by the observation that EC nuclei showed strong SREBP staining in human atherosclerotic lesions. The current studies suggest a novel role for endothelial cholesterol depletion and subsequent SREBP activation in inflammatory processes in which phospholipid oxidation products accumulate.
Key words: oxidized phospholipids • interleukin-8 • endothelium • caveolae • cholesterol
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