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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:871.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Anti–LOX-1 Rescues Endothelial Function in Coronary Arterioles in Atherosclerotic ApoE Knockout Mice

Xiangbin Xu; Xue Gao; Barry J. Potter; Ji-Min Cao; Cuihua Zhang

From the Department of Veterinary Physiology & Pharmacology (X.X., X.G., C.Z.), Texas A&M University, College Station, Tex; the Department of Physiology (B.J.P.), LSU Health Sciences Center, New Orleans, La; and the Department of Physiology (J.-M.C.), Peking Union Medical College, Beijing, P.R. China.

Correspondence to Cuihua Zhang, MD, PhD, Department of Veterinary Physiology & Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843-4466. E-mail czhang{at}cvm.tamu.edu

Background— We hypothesized that atherosclerosis inhibits NO-mediated endothelium-dependent dilation of coronary arterioles through interaction of ox-LDL with its receptor, LOX-1, through the production of O₂ÿ^– in endothelial cells.

Methods and Results— We assessed the role of ox-LDL in endothelial dysfunction in a murine model of atherosclerosis (ApoE KO mice). Coronary arterioles from WT control and ApoE KO mice were isolated and pressurized without flow. Although dilation of vessels to endothelium-independent vasodilator SNP was not altered between ApoE KO and WT mice, dilation to the endothelium-dependent agonist, ACh was reduced in ApoE KO versus WT mice. Impaired vasodilation to ACh in ApoE KO mice is partially restored by NAD(P)H oxidase inhibitor, apocynin or DPI. Messenger RNA expression for NAD(P)H oxidases was higher in ApoE KO mice than that in WT and anti–LOX-1 treated ApoE KO mice. Anti–LOX-1, given in vivo, restored NO-mediated coronary arteriolar dilation in ApoE KO mice, but did not affect the endothelium-dependent vasodilation in controls.

Conclusions— These results suggest that ox-LDL impairs endothelium-dependent NO-mediated dilation of coronary arterioles by activation of a signaling cascade involving LOX-1 and NAD(P)H oxidase expression.

We examined the role of LOX-1 in endothelial dysfunction in ApoE KO mice. Impaired vasodilation to ACh in ApoE KO mice is partially restored by NAD(P)H oxidase inhibitor. Anti–LOX-1 restored vasodilation to ACh; reduced mRNA expression of NAD(P)H oxidase and O₂ÿ^– production. LOX-1 is implicated in endothelial dysfunction.

Key Words: atherosclerosis • coronary artery disease • endothelial function • microcirculation • reactive oxygen species