title: Calcium [corrected] channel blockers reduce angiotensin II-induced superoxide generation and inhibit lectin-like oxidized low-density lipoprotein receptor-1 expression in endothelial cells.
abstract: Calcium channel blockers have been shown to limit the progression of atherosclerosis and decrease the incidence of cardiovascular events. To investigate vasoprotective effects beyond the blood pressure-lowering effects of these agents, amlodipine (10(-6) mol/) and manidipine (10(-6) mol/l) were used to pretreat angiotensin (Ang) II-stimulated rat cultured aortic endothelial cells. A 3-h period of Ang II treatment enhanced superoxide generation and the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase protein, as detected by dihydroethidium staining and Western blotting, respectively. Pretreatment with amlodipine or manidipine attenuated the increased production of superoxide and the overexpression of NADPH oxidase. The enhanced expression of heme oxygenase-1 (HO-1) mRNA induced by Ang II was further increased by amlodipine, whereas pretreatment with manidipine led to a reduction in the expression of HO-1. Furthermore, Ang II increased vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), and monocyte chemoattractant protein-1 (MCP-1) mRNA levels, as determined by reverse transcription (RT)-polymerase chain reaction (PCR). Pretreatment with either amlodipine or manidipine decreased the overexpression of VCAM-1, ICAM-1, and MCP-1. We also demonstrated that amlodipine or manidipine prevented the Ang II-induced increase in lectin-like oxidized low-density lipoprotein receptor1 (LOX-1) content, thereby restoring control levels. These observations showed that amlodipine and manidipine reduced superoxide generation by the inhibition of the overexpression of NADPH oxidase in Ang II-stimulated endothelial cells. Such antioxidant effects of these agents might in turn have led to a decrease in the expression of VCAM-1, ICAM-1 and MCP-1. The salutary effects of calcium channel blockers in atherogenesis include the inhibition of the expression of LOX-1.
authors.affiliation: Department of Clinical Pharmacology, Kyoto Pharmaceutical University, 5 Misasagi Nakauchi-cho, Yamashima-ku, Kyoto 607-8414, Japan. toba@mb.kyoto-phu.ac.jp
authors.forename: Hiroe
authors.initials: H
authors.lastname: Toba
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shimizu
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Miki
authors.forename: Riyako
authors.initials: R
authors.lastname: Inoue
authors.forename: Akiko
authors.initials: A
authors.lastname: Yoshimura
authors.forename: Rie
authors.initials: R
authors.lastname: Tsukamoto
authors.forename: Naoki
authors.initials: N
authors.lastname: Sawai
authors.forename: Miyuki
authors.initials: M
authors.lastname: Kobara
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nakata
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001011:Aorta / Q000166:cytology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015815:Cell Adhesion Molecules / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects*; D051547:Heme Oxygenase-1 / Q000187:drug effects; D007249:Inflammation / Q000378:metabolism; D008297:Male; D019255:NADPH Oxidases / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D012333:RNA, Messenger / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D051127:Scavenger Receptors, Class E / Q000187:drug effects*; D013481:Superoxides / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; C495137:OLR1 protein, human; D012333:RNA, Messenger; D051127:Scavenger Receptors, Class E; D013481:Superoxides; D000804:Angiotensin II; D051547:Heme Oxygenase-1; D019255:NADPH Oxidases