Published online before print January 26, 2006, doi: 10.1161/01.RES.0000205846.46812.be
© 2006 American Heart Association, Inc.
Molecular Medicine |
High-Density Lipoprotein Hydrolysis by Endothelial Lipase Activates PPAR
A Candidate Mechanism for High-Density Lipoprotein-Mediated Repression of Leukocyte Adhesion
From the Donald W. Reynolds Cardiovascular Clinical Research Center (W.A., G.O., V.N., O.Z., J.P.), Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; the Department of Medicine (D.J.R.), University of Pennsylvania, Philadelphia; and the School of Pharmacy (L.A.), University of Southern California, Los Angeles.
Correspondence to Jorge Plutzky, MD, 77 Avenue Louis Pasteur, NRB 740, Brigham and Women’s Hospital, Boston, MA 02115. E-mail jplutzky{at}rics.bwh.harvard.edu
Although high-density lipoprotein (HDL) is known to inhibit endothelial adhesion molecule expression, the mechanism for this anti-inflammatory effect remains obscure. Surprisingly, we observed that HDL no longer decreased adhesion of U937 monocytoid cells to tumor necrosis factor (TNF)
-stimulated human endothelial cells (EC) in the presence of the general lipase inhibitor tetrahydrolipstatin. In considering endothelial mechanisms responsible for this effect, we found that endothelial lipase (EL) overexpression in both EC and non-EL-expressing NIH/3T3 mouse embryonic fibroblasts cells significantly decreased TNF-induced VCAM1 expression and promoter activity in a manner dependent on HDL concentration and intact EL activity. Given recent evidence for lipolytic activation of peroxisome proliferator-activated receptors (PPARs)—nuclear receptors implicated in metabolism, atherosclerosis, and inflammation—we hypothesized HDL hydrolysis by EL is an endogenous endothelial mechanism for PPAR activation. In both EL-transfected NIH cells and bovine EC, HDL significantly increased PPAR ligand binding domain activation in the order PPAR->>-
>-
. Moreover, HDL stimulation induced expression of the canonical PPAR-target gene acyl-CoA-oxidase (ACO) in a PPAR-dependent manner in ECs. Conditioned media from EL-adenovirus transfected cells but not control media exposed to HDL also activated PPAR. PPAR activation by EL was most potent with HDL as a substrate, with lesser effects on LDL and VLDL. Finally, HDL inhibited leukocyte adhesion to TNF-stimulated ECs isolated from wild-type but not PPAR-deficient mice. This data establishes HDL hydrolysis by EL as a novel, distinct natural pathway for PPAR activation and identifies a potential mechanism for HDL-mediated repression of VCAM1 expression, with significant implications for both EL and PPARs in inflammation and vascular biology.
Key Words: adhesion molecules • endothelial cells • HDL cholesterol • high-density lipoproteins • lipase • PPARs • transcriptional regulation
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