title: Inhibition of Fas-associated apoptosis in granulation tissue cells accompanies attenuation of postinfarction left ventricular remodeling by olmesartan.
abstract: Blockade of angiotensin II type 1 receptor (AT1) signaling attenuates heart failure following myocardial infarction (MI), perhaps through reduction of fibrosis in the noninfarcted myocardium. However, its specific effect on the infarct tissue itself has not been fully clarified, which we examined in the present study. After MI induction in mice, treatment with the AT1 blocker olmesartan, beginning on the 3rd day post-MI, significantly improved survival (94%) 4 wk post-MI, compared with saline (53%) and hydralazine (73%). Olmesartan-treated mice also showed significant attenuation of left ventricular dilatation and dysfunction, as well as significantly greater infarct wall thickness, although the absolute size of the infarct scar was unchanged. In addition, significantly greater numbers of nonmyocytes (mainly vascular cells and myofibroblasts) were present within the infarct scar in olmesartan-treated hearts. Ten days post-MI, apoptosis among granulation tissue cells was significantly suppressed in the olmesartan-treated hearts, where expression of Fas, Bax, procaspase-3, and Daxx and activation of caspase-3, c-Jun NH(2)-terminal kinase, and c-Jun were all significantly attenuated. By contrast, expression of Fas ligand, Bcl-2, and Fas-associated death domain and activation of caspase-8 were unaffected, suggesting olmesartan exerts a negative regulatory effect on the alternate pathway downstream of Fas receptor. In vitro, olmesartan dose-dependently inhibited Fas-mediated apoptosis in granulation tissue-derived myofibroblasts. The present study proposes this antiapoptotic effect as another important mechanism for an AT1 blocker in improving post-MI ventricular remodeling, as well as its antifibrotic effect, and also suggests a significant link between renin-angiotensin and Fas/Fas ligand systems in postinfarction hearts.
authors.affiliation: Second Department of Internal Medicine, Gifu University School of Medicine, 1-1 Yanagito, Gifu 501-1194, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kanamori
authors.forename: Genzou
authors.initials: G
authors.lastname: Takemura
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Li
authors.forename: Hideshi
authors.initials: H
authors.lastname: Okada
authors.forename: Rumi
authors.initials: R
authors.lastname: Maruyama
authors.forename: Takuma
authors.initials: T
authors.lastname: Aoyama
authors.forename: Shusaku
authors.initials: S
authors.lastname: Miyata
authors.forename: Masayasu
authors.initials: M
authors.lastname: Esaki
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ogino
authors.forename: Munehiro
authors.initials: M
authors.lastname: Nakagawa
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: Hisayoshi
authors.initials: H
authors.lastname: Fujiwara
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000150:complications / Q000473:pathology* / Q000503:physiopathology*; D013777:Tetrazoles / Q000494:pharmacology*; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D020257:Ventricular Remodeling / Q000187:drug effects*; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D013777:Tetrazoles; D019014:fas Receptor; C437965:olmesartan