Scavenger receptor BI prevents nitric oxide-induced cytotoxicity and endotoxin-induced death.
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.
Department of Pediatrics, University of Kentucky Medical School, Lexington, KY, USA. xli2@email.uky.edu
Xiang-An
XA
Li
Ling
L
Guo
Reto
R
Asmis
Mariana
M
Nikolova-Karakashian
Eric J
EJ
Smart
D000595:Amino Acid Sequence; D000818:Animals; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D016466:CHO Cells; D016923:Cell Death / Q000187:drug effects*; D017124:Conserved Sequence; D006224:Cricetinae; D004731:Endotoxins / Q000633:toxicity; D017353:Gene Deletion; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000633:toxicity*; D011994:Recombinant Proteins / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D018955:CD36 Antigens; D004731:Endotoxins; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D009569:Nitric Oxide