title: Blockade by nifedipine of advanced glycation end product-induced CD40-CD40 ligand interaction in endothelial cells.
abstract: Advanced glycation end products (AGEs), the senescent macroprotein derivatives that form in increased amounts in diabetes, have been implicated in the pathogenesis of accelerated atherosclerosis. There is a growing body of evidence that CD40-CD40 ligand (CD40L) interaction also plays an important role in atherogenesis. However, the effects of AGEs on CD40-CD40L signaling in endothelial cells (ECs) remain to be elucidated. In this study, we investigated (i) whether injection of AGE-proteins to normal rats stimulates CD40L expression on circulating platelets and (ii) whether AGEs up-regulate CD40 mRNA levels in cultured ECs. We further examined the effects of nifedipine, one of the most popular dihydropyridine-based calcium antagonists, on CD40 gene expression in AGE-exposed ECs. Platelet surface CD40L expression was increased in AGE-bovine serum albumin (AGE-BSA)-injected rats, compared with nonglycated BSA administration. AGEs were found to induce up-regulation of CD40 mRNA levels in ECs, which were significantly blocked by nifedipine. These results suggest that AGEs could enhance CD40-CD40L interaction, thereby promoting atherosclerosis in diabetes. Blockade of CD40-CD40L signaling in ECs may be a molecular target for the vasculoprotective property of nifedipine.
authors.affiliation: Department of Medicine, Kurume University School of Medicine, Kurume, Japan. shoichi@med.kurume-u.ac.jp
authors.forename: S
authors.initials: S
authors.lastname: Yamagishi
authors.forename: S
authors.initials: S
authors.lastname: Kikuchi
authors.forename: K
authors.initials: K
authors.lastname: Takenaka
authors.forename: M
authors.initials: M
authors.lastname: Takeuchi
mesh_terms: D000818:Animals; D019013:CD40 Antigens / Q000096:biosynthesis* / Q000235:genetics; D023201:CD40 Ligand / Q000096:biosynthesis*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D009543:Nifedipine / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D019013:CD40 Antigens; D002121:Calcium Channel Blockers; D017127:Glycation End Products, Advanced; D012333:RNA, Messenger; D023201:CD40 Ligand; D009543:Nifedipine