title: Nifedipine inhibits tumor necrosis factor-alpha-induced monocyte chemoattractant protein-1 overexpression by blocking NADPH oxidase-mediated reactive oxygen species generation.
abstract: There is a growing body of evidence that dihydropyridine-based calcium antagonists (DHPs) improve endothelial function, thus slowing the development and progression of atherosclerosis. However the molecular mechanisms by which DHPs normalize endothelial dysfunction, an initial step in atherosclerosis, are not fully understood. Monocyte recruitment and firm adhesion to endothelial cells play a central role in the pathogenesis of atherosclerosis. In this study, we investigated whether nifedipine, one of the most popular DHPs, could inhibit tumor necrosis factor-alpha (TNF-alpha)-induced reactive oxygen species (ROS) generation and subsequent monocyte chemoattractant protein-1 (MCP-1) expression in human umbilical vein endothelial cells (HUVEC). TNF-alpha significantly increased intracellular ROS generation in HUVEC, which was completely blocked by nifedipine. Nifedipine completely inhibited TNF-alpha-induced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in HUVEC. Furthermore, nifedipine was found to significantly inhibit upregulation of MCP-1 messenger RNA levels in TNF-alpha-exposed HUVEC. The results demonstrate that nifedipine could inhibit TNF-alpha-induced MCP-1 overexpression in HUVEC by suppressing NADPH oxidase-mediated ROS generation. Our present study suggests that nifedipine may play a protective role in the development and progression of atherosclerosis through its antioxidative properties.
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: Y
authors.initials: Y
authors.lastname: Inagaki
authors.forename: S
authors.initials: S
authors.lastname: Kikuchi
mesh_terms: D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D017931:DNA Primers; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004996:Ethidium / Q000031:analogs & derivatives*; D005456:Fluorescent Dyes; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology*
chemical_list: D002121:Calcium Channel Blockers; D018932:Chemokine CCL2; D017931:DNA Primers; D005456:Fluorescent Dyes; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C067883:dihydroethidium; D019255:NADPH Oxidases; D004996:Ethidium; D009543:Nifedipine