Published online before print May 3, 2007, doi: 10.1161/CIRCRESAHA.107.149724
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© 2007 American Heart Association, Inc.
Integrative Physiology |
Deletion of LOX-1 Reduces Atherogenesis in LDLR Knockout Mice Fed High Cholesterol Diet
From Cardiovascular Medicine (J.L.M., C.P.H., J.C., A.D., P.L.H., M.T., T.S.), Gene Therapy Program, University of Arkansas for Medical Sciences, Little Rock, Ark; National Cardiovascular Center (N.S., F.S., K.I., T.S.), Osaka, Japan; Kumamoto University (M.T., H. Satoh), Kumamoto, Japan; Chugai Research Institute For Medical Science (Y.K., K.J.), Japan; Obihiro University of Agriculture and Veterinary Medicine (H. Suzuki), Japan; and the National Center for Toxicology Research (L.S., R.B.), Jefferson, Ark.
Correspondence to J.L. Mehta, MD, PhD, Cardiovascular Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205. E-mail MehtaJL{at}uams.edu
Atherosclerosis is associated with oxidative stress and inflammation, and upregulation of LOX-1, an endothelial receptor for oxidized LDL (oxLDL). Here, we describe generation of LOX-1 knockout (KO) mice in which binding of oxLDL to aortic endothelium was reduced and endothelium-dependent vasorelaxation preserved after treatment with oxLDL (P<0.01 versus wild-type mice). To address whether endothelial functional preservation might lead to reduction in atherogenesis, we crossed LOX-1 KO mice with LDLR KO mice and fed these mice 4% cholesterol/10% cocoa butter diet for 18 weeks. Atherosclerosis was found to cover 61±2% of aorta in the LDLR KO mice, but only 36±3% of aorta in the double KO mice. Luminal obstruction and intima thickness were significantly reduced in the double KO mice (versus LDLR KO mice). Expression of redox-sensitive NF-
B and the inflammatory marker CD68 in LDLR KO mice was increased (P<0.01 versus wild-type mice), but not in the double KO mice. On the other hand, antiinflammatory cytokine IL-10 expression and superoxide dismutase activity were low in the LDLR KO mice (P<0.01 versus wild-type mice), but not in the double KO mice. Endothelial nitric oxide synthase expression was also preserved in the double KO mice. The proinflammatory signal MAPK P38 was activated in the LDLR KO mice, and LOX-1 deletion reduced this signal. In conclusion, LOX-1 deletion sustains endothelial function leading to a reduction in atherogenesis in association with reduction in proinflammatory and prooxidant signals.
Key Words: atherosclerosis • oxidative stress • inflammation • LOX-1
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