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Olmesartan prevents cardiac rupture in mice with myocardial infarction by modulating growth differentiation factor 15 and p53
Author(s) -
Chen Baihe,
Lu Di,
Fu Yujuan,
Zhang Jingwen,
Huang Xiaobo,
Cao Shiping,
Xu Dingli,
Bin Jianping,
Kitakaze Masafumi,
Huang Qiaobing,
Liao Yulin
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12736
Subject(s) - tunel assay , olmesartan , angiotensin ii , myocardial infarction , apoptosis , medicine , endocrinology , receptor , downregulation and upregulation , gdf15 , pharmacology , cardiology , biology , immunohistochemistry , biochemistry , gene , blood pressure
Background and Purpose Cardiac rupture is a catastrophic complication that occurs after acute myocardial infarction ( MI ) and, at present, there are no effective pharmacological strategies for preventing this condition. Here we investigated the effect of the angiotensin II receptor blocker olmesartan ( O lm) on post‐infarct cardiac rupture and its underlying mechanisms of action. Experimental Approach C 57 B l/6 mice with MI were treated with O lm, aldosterone ( A ldo) or vehicle. Cultured neonatal cardiomyocytes and fibroblasts were exposed to normoxia or anoxia and treated with angiotensin II ( A ng II ), RNH 6270 (active ingredient of O lm) or A ldo. Key Results The mortality rate and incidence of cardiac rupture in MI mice during the first week in the O lm‐treated group were significantly lower than in the vehicle‐treated group. O lm or RNH 6270 reduced myeloperoxidase staining in the infarcted myocardium, decreased apoptosis in cultured cardiomyocytes and fibroblasts, as assessed by H oechst staining and TUNEL assay, attenuated the accumulation of p53 and phosphorylated p53 and cleaved caspase 3 induced by MI or A ng II, as assessed by Western blotting, and up‐regulated growth differentiation factor‐15 ( GDF ‐15). In cultured cardiomyocytes and fibroblasts, treatment with A ng II, Aldo or anoxia significantly down‐regulated the expression of GDF ‐15. Conclusions and Implications O lm prevents cardiac rupture through inhibition of apoptosis and inflammation, which is attributable to the down‐regulation of p53 activity and up‐regulation of GDF ‐15. Our findings suggest that early administration of an AT 1 receptor anatagonist to patients with acute MI is a potential preventive approach for cardiac rupture.