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J. Biol. Chem., Vol. 280, Issue 19, 19087-19096, May 13, 2005

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A Novel Ligand-independent Apoptotic Pathway Induced by Scavenger Receptor Class B, Type I and Suppressed by Endothelial Nitric-oxide Synthase and High Density Lipoprotein^*

Xiang-An Li, Ling Guo, James L. Dressman, Reto Asmis, and Eric J. Smart¶

From the Departments of Pediatrics and Medicine, University of Kentucky Medical School, Lexington, Kentucky 40536-0230

Scavenger receptor class B, type I (SR-BI)/ApoE double null mice develop severe atherosclerosis within 4 weeks, whereas ApoE null mice take several months to develop the disease, indicating that SR-BI plays a pivotal role in atherosclerosis. Importantly, SR-BI/ApoE double null mice have lower plasma cholesterol levels than ApoE null mice, suggesting involvement of a non-lipids mechanism. In the present study, we revealed a novel ligand-independent apoptotic pathway induced by SR-BI, and regulated by endothelial nitric-oxide synthase (eNOS) and high density lipoprotein (HDL). SR-BI significantly induces apoptosis in three independent cell systems. In contrast to known ligand-dependent apoptotic pathways, SR-BI-induced apoptosis is ligand-independent. We further showed that SR-BI-induced apoptosis is suppressed by eNOS and HDL. By using a single site mutation, we demonstrated that SR-BI induces apoptosis through a highly conserved CXXS redox motif. We finally demonstrated that SR-BI-induced apoptosis is via the caspase-8 pathway. We hypothesize that in healthy cells, the SR-BI apoptotic pathway is turned off by eNOS and HDL which prevents inappropriate apoptotic damage to the vascular wall. When HDL levels are low, oxidative stress causes the relocation of eNOS away from caveolae, which turns on SR-BI-induced apoptosis and rapidly clears damaged cells to prevent further inflammatory damage to neighboring cells. The current studies offer a new paradigm in which to study the non-cholesterol effects of SR-BI, HDL, and eNOS on the development of atherosclerosis and potentially other cardiovascular diseases.

Received for publication, January 25, 2005 , and in revised form, March 2, 2005.

^* This work was supported by Grants HL64056, HL62844, and HL68509 from the NHLBI, National Institutes of Health (to E. J. S.) and by Grant 0530241N from the American Heart Association (to X.-A. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Pediatrics, University of Kentucky, 423 Sanders-Brown, 800 Limestone St., Lexington, KY 40536-0230. Tel.: 859-323-6412; Fax: 859-257-2120; E-mail: ejsmart{at}uky.edu.

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