Nifedipine inhibits tumor necrosis factor-alpha-induced upregulation of monocyte chemoattractant protein-1 mRNA levels by suppressing CD40 expression in endothelial cells.
There is a growing body of evidence that dihydropyridine-based calcium antagonists (DHPs) improve endothelial function, thus slowing the development and progression of atherosclerosis. We have previously shown that nifedipine, one of the most popular DHPs, inhibits tumor necrosis factor-alpha (TNF-alpha)-induced reactive oxygen species generation and subsequent monocyte chemoattractant protein-1 (MCP-1) expression in human umbilical vein endothelial cells (HUVEC). However, the molecular mechanism underlying this phenomenon remains to be elucidated. CD40, a cell surface receptor that belongs to TNF-alpha receptor, has been associated with the pathogenesis of chronic inflammatory diseases such as atherosclerosis. In this study, we investigated the involvement of CD40 in MCP-1 suppression by nifedipine in TNF-alpha-exposed HUVEC. Nifedipine completely inhibited TNF-alpha-induced upregulation of CD40 mRNA levels in HUVEC. Furthermore, antibody against human CD40 was found to significantly inhibit upregulation of MCP-1 mRNA levels in TNF-alpha-exposed HUVEC. These results demonstrate that nifedipine could inhibit the TNF-alpha-induced upregulation of MCP-1 mRNA levels via suppression of CD40 expression in HUVEC. Our present study suggests that blockade of CD40 signaling in endothelial cells may be a molecular target for the vasculoprotective property of nifedipine.
Yamagishi
S
S
Department of Medicine, Kurume University School of Medicine, Kurume, Japan. shoichi@med.kurume-u.ac.jp
Takeuchi
M
M
D019013:CD40 Antigens / Q000096:biosynthesis* / Q000235:genetics; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D009543:Nifedipine / Q000494:pharmacology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology; D015854:Up-Regulation
D019013:CD40 Antigens; D002121:Calcium Channel Blockers; D018932:Chemokine CCL2; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009543:Nifedipine