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(Circulation Research. 2006;98:e60.)
© 2006 American Heart Association, Inc.

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Scavenger Receptor BI Prevents Nitric Oxide–Induced Cytotoxicity and Endotoxin-Induced Death

Xiang-An Li, Ling Guo, Reto Asmis, Mariana Nikolova-Karakashian, Eric J. Smart

From the Departments of Pediatrics (X.-A.L., L.G., E.J.S.) and Physiology (M.N.-K.), University of Kentucky Medical School, Lexington; and Division of Nephrology (R.A.), University of Texas Health Science Center at San Antonio.

Correspondence to Xiang-An Li, University of Kentucky, Department of Pediatrics, 423A Sanders Brown Building, 800 S Limestone St, Lexington, KY 40536-0230. E-mail xli2{at}email.uky.edu

Nitric oxide (NO)-induced oxidative stress contributes to a variety of diseases. Although numerous mechanisms have been described controlling the production of NO, the mechanisms to prevent NO-induced cytotoxicity after NO synthesis are largely unknown. Here we report that scavenger receptor BI (SR-BI) prevents NO-induced cytotoxicity. Using CHO cell lines expressing wild-type and single-site mutant SR-BI protein, we demonstrate that SR-BI prevents NO-induced cytotoxicity and that a highly conserved CXXS redox motif is required for the anti-NO cytotoxicity activity of SR-BI. Using genetically manipulated mice, we demonstrate that SR-BI–null mice have a 3- to 4-fold increase in tyrosine nitrated proteins in aorta and liver compared with wild-type littermates, indicating that expression of SR-BI prevents peroxynitrite formation in vivo. Using lipopolysacharide (LPS)-challenged mice as an in vivo model of NO-induced cytotoxicity, we found that a single dose of LPS (120 000 U/g IP) induced 90% fatality of SR-BI–null mice within 3 days, whereas all of the wild-type littermates survived (n=20), demonstrating that SR-BI is highly protective against NO cytotoxicity in vivo. Importantly, SR-BI prevents LPS-induced death without eliminating NO production, suggesting that SR-BI prevents NO-induced cytotoxicity post-NO synthesis. Our study describes a novel observation that may shed new light on the treatment of nitric oxidative stress–associated diseases, such as septic shock.

Key Words: nitric oxide • scavenger receptor BI • nitric oxidative stress • endotoxin

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