title: Amlodipine inhibits granulation tissue cell apoptosis through reducing calcineurin activity to attenuate postinfarction cardiac remodeling.
abstract: Although amlodipine, a long-acting L-type calcium channel blocker, reportedly prevents left ventricular remodeling and dysfunction after myocardial infarction, the mechanism responsible is not yet well understood. Myocardial infarction was induced in mice by ligating the left coronary artery. Treatment of mice with amlodipine (10 mg x kg(-1) x day(-1)), beginning on the third day postinfarction, significantly improved survival and attenuated left ventricular dilatation and dysfunction 4 wk postinfarction compared with treatment with saline or hydralazine. Although infarct sizes did not differ among the groups, the infarcted wall thickness was greater and the infarct segment length was smaller in the amlodipine-treated group, and cellular components, including vessels and myofibroblasts, were abundant within the infarcted area. Ten days postinfarction (the subacute stage), the proliferation of granulation tissue cells in the infarcted area was similar among the groups, but the incidence of apoptosis was significantly lower in the amlodipine-treated group, where Bad, a proapoptotic Bcl-2 family protein, was significantly phosphorylated (inactivated). Calcineurin, which dephosphorylates (activates) Bad, was upregulated in infarcted hearts, but its levels were significantly reduced by amlodipine treatment. In vitro, Fas stimulation augmented calcineurin activity and induced apoptosis among infarct tissue-derived myofibroblasts; both of those effects were strongly inhibited by amlodipine, two other calcium channel blockers (verapamil or nifedipine), and two calcineurin inhibitors (cyclosporin A or FK-506). Amlodipine inhibits Fas-mediated granulation tissue cell apoptosis in infarcted hearts, possibly by attenuating the activities of calcineurin and Bad. These findings may provide new insight into the mechanism by which calcium channel blockers attenuate postinfarction cardiac remodeling and dysfunction.
authors.affiliation: Second Department of Internal Medicine, Gifu University School of Medicine, Gifu, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ogino
authors.forename: Genzou
authors.initials: G
authors.lastname: Takemura
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kanamori
authors.forename: Hideshi
authors.initials: H
authors.lastname: Okada
authors.forename: Rumi
authors.initials: R
authors.lastname: Maruyama
authors.forename: Shusaku
authors.initials: S
authors.lastname: Miyata
authors.forename: Masayasu
authors.initials: M
authors.lastname: Esaki
authors.forename: Munehiro
authors.initials: M
authors.lastname: Nakagawa
authors.forename: Takuma
authors.initials: T
authors.lastname: Aoyama
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ushikoshi
authors.forename: Masanori
authors.initials: M
authors.lastname: Kawasaki
authors.forename: Shinya
authors.initials: S
authors.lastname: Minatoguchi
authors.forename: Takako
authors.initials: T
authors.lastname: Fujiwara
authors.forename: Hisayoshi
authors.initials: H
authors.lastname: Fujiwara
mesh_terms: D017311:Amlodipine / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D015220:Calcium Channels / Q000378:metabolism; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000601:surgery; D016572:Cyclosporine / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006097:Granulation Tissue / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006830:Hydralazine / Q000494:pharmacology; D008026:Ligation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D010766:Phosphorylation; D012107:Research Design; D016559:Tacrolimus / Q000494:pharmacology; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*; D051025:bcl-Associated Death Protein / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: C494820:Bad protein, mouse; D065095:Calcineurin Inhibitors; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004791:Enzyme Inhibitors; C491899:Fas protein, mouse; D014665:Vasodilator Agents; D051025:bcl-Associated Death Protein; D019014:fas Receptor; D017311:Amlodipine; D006830:Hydralazine; D016572:Cyclosporine; D019703:Calcineurin; D002118:Calcium; D016559:Tacrolimus