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(Circulation Research. 2009;104:619.)
© 2009 American Heart Association, Inc.

Molecular Medicine

Mediation of Electronegative Low-Density Lipoprotein Signaling by LOX-1

A Possible Mechanism of Endothelial Apoptosis

Jonathan Lu, Jun-Hai Yang, Alan R. Burns, Hsin-Hung Chen, Daming Tang, Jeffrey P. Walterscheid, Shinichi Suzuki, Chao-Yuh Yang, Tatsuya Sawamura, Chu-Huang Chen

From the Department of Medicine (J.L., A.R.B., H.-H.C., D.T., J.P.W., C.-Y.Y., C.-H.C.), Baylor College of Medicine, Houston, Tex; Cardiovascular Research Laboratory (J.-H.Y.), School of Medicine, University of California, Los Angeles; College of Optometry (A.R.B.), University of Houston, Tex; Department of Cardiovascular Surgery (S.S.), Yokohama City University Medical Center, Japan; Department of Bioscience (T.S.), National Cardiovascular Center Research Institute, Osaka, Japan; and Department of Medicine (C.-H.C.), China Medical University Hospital, Taichung, Taiwan.

Correspondence to Chu-Huang Chen, MD, PhD, 6565 Fannin St, MS A-601, Houston, TX 77030. E-mail cchen{at}bcm.tmc.edu

The lectin-like oxidized LDL receptor LOX-1 mediates endothelial cell (EC) uptake of experimentally prepared copper-oxidized LDL (oxLDL). To confirm the atherogenic role of this receptor cloned against copper-oxLDL, we examined whether it mediates EC uptake of L5, an electronegative LDL abundant in dyslipidemic but not normolipidemic human plasma. Hypercholesterolemic (LDL-cholesterol, >160 mg/dL) human LDL was fractionated into L1–L5, increasingly electronegative, by ion-exchange chromatography. In cultured bovine aortic ECs (BAECs), L5 upregulated LOX-1 and induced apoptosis. Transfection of BAECs with LOX-1–specific small interfering RNAs (siLOX-1) minimized baseline LOX-1 production and restrained L5-induced LOX-1 upregulation. Internalization of labeled L1–L5 was monitored in BAECs and human umbilical venous ECs by fluorescence microscopy. LOX-1 knockdown with siLOX-1 impeded the endocytosis of L5 but not L1–L4. In contrast, blocking LDL receptor with RAP (LDL receptor–associated protein) stopped the internalization of L1–L4 but not L5. Although chemically different, L5 and oxLDL competed for EC entry through LOX-1. Via LOX-1, L5 signaling hampered Akt phosphorylation and suppressed EC expression of fibroblast growth factor-2 and Bcl-2. L5 also selectively inhibited Bcl-xL expression and endothelial nitric oxide synthase phosphorylation but increased synthesis of Bax, Bad, and tumor necrosis factor-. Blocking Akt phosphorylation with wortmannin increased LOX-1 expression, suggesting a modulatory role of Akt in LOX-1 synthesis; L5 upregulated LOX-1 by dephosphorylating Akt. Because endothelial nitric oxide synthase and Bcl-2 activities are Akt-dependent, L5 impairs Akt-mediated growth and survival signals in vascular ECs by way of LOX-1. Thus, the L5/LOX-1 complex may play a critical role in atherogenesis and illuminate important targets for disease intervention.

Key Words: apoptosis • atherosclerosis • endothelium • lipoproteins • receptors

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