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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:816.)
© 2003 American Heart Association, Inc.

Vascular Biology

LOX-1, an Oxidized LDL Endothelial Receptor, Induces CD40/CD40L Signaling in Human Coronary Artery Endothelial Cells

Dayuan Li; Ling Liu; Hongjiang Chen; Tatsuya Sawamura; Jawahar L. Mehta

From the Departments of Medicine and Physiology and Biophysics (D.L., L.L., J.L.M.), University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, and the Department of Bioscience (T.S.), National Cardiovascular Center Research Institute, Osaka, Japan.

Correspondence to J.L. Mehta, MD, PhD, Department of Internal Medicine, University of Arkansas for Medical Sciences, 4301 W Markham St, #532, Little Rock, AR 72205. E-mail mehtajl{at}uams.edu

Background— Despite increasing appreciation that atherogenesis involves participation of inflammatory cells, information on mediators of communication between different constituents of atherosclerotic plaque remain incomplete. We examined the role of LOX-1, a receptor for oxidized (ox) LDL, in the expression of CD40/CD40L in cultured human coronary artery endothelial cells (HCAECs).

Methods and Results— We observed that ox-LDL increased the expression of CD40 and CD40L in a concentration (10 to 80 µg/mL)- and time (1 to 24 hours)- dependent manner. These effects of ox-LDL were mediated by activation of LOX-1, because pretreatment of HCAECs with a blocking antibody to LOX-1 (JTX92) prevented the expression of CD40 and CD40L in response to ox-LDL (P<0.01). In parallel experiments, HCAECs were incubated with the protein kinase C (PKC) inhibitor bisindolylmaleimide I, and the cells were then exposed to ox-LDL. Both LOX-1 antibody and the PKC inhibitor inhibited PKC activation in response to ox-LDL (P<0.01). The PKC inhibitor also blocked the effects of ox-LDL on the expression of CD40 and CD40L (P<0.01). In additional experiments, we found that it is the PKC, but not PKCß and PKC, isoform that mediated ox-LDL–induced CD40 and CD40L upregulation. Further experiments showed that upregulation of CD40 mediated induction of proinflammatory genes, because CD40 antibody markedly reduced ox-LDL–induced TNF- generation and P-selectin expression, whereas nonspecific mouse IgG had no effect.

Conclusions— These findings indicate that ox-LDL through its receptor LOX-1 triggers the CD40/CD40L signaling pathway that activates the inflammatory reaction in HCAECs. These observations provide novel insight into ox-LDL–mediated inflammation in atherosclerosis.

Key Words: CD40/CD40L • endothelial cells • LOX-1 • oxidized LDL • protein kinase

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