title: LOX-1, an oxidized LDL endothelial receptor, induces CD40/CD40L signaling in human coronary artery endothelial cells.
abstract: 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).
  
  
  RESULTS
  We observed that ox-LDL increased the expression of CD40 and CD40L in a concentration (10 to 80 microg/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 PKCalpha, but not PKCbeta and PKCgamma, 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-alpha 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.
authors.affiliation: Department of Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA.
authors.forename: Dayuan
authors.initials: D
authors.lastname: Li
authors.forename: Ling
authors.initials: L
authors.lastname: Liu
authors.forename: Hongjiang
authors.initials: H
authors.lastname: Chen
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Sawamura
authors.forename: Jawahar L
authors.initials: JL
authors.lastname: Mehta
mesh_terms: D001161:Arteriosclerosis / Q000209:etiology; D019013:CD40 Antigens / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D023201:CD40 Ligand / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured / Q000187:drug effects / Q000502:physiology; D003331:Coronary Vessels / Q000166:cytology* / Q000502:physiology; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D051571:Protein Kinase C-alpha; D021122:Protein Subunits; D011973:Receptors, LDL / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014657:Vasculitis / Q000139:chemically induced / Q000378:metabolism
chemical_list: D019013:CD40 Antigens; D004791:Enzyme Inhibitors; D008077:Lipoproteins, LDL; D021122:Protein Subunits; D011973:Receptors, LDL; D014409:Tumor Necrosis Factor-alpha; C099252:oxidized low density lipoprotein; D023201:CD40 Ligand; C496628:PRKCA protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha