title: Olmesartan prevents cardiac rupture in mice with myocardial infarction by modulating growth differentiation factor 15 and p53.
abstract: OBJECTIVE
  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 (Olm) on post-infarct cardiac rupture and its underlying mechanisms of action.
  
  
  METHODS
  C57Bl/6 mice with MI were treated with Olm, aldosterone (Aldo) or vehicle. Cultured neonatal cardiomyocytes and fibroblasts were exposed to normoxia or anoxia and treated with angiotensin II (Ang II), RNH6270 (active ingredient of Olm) or Aldo.
  
  
  RESULTS
  The mortality rate and incidence of cardiac rupture in MI mice during the first week in the Olm-treated group were significantly lower than in the vehicle-treated group. Olm or RNH6270 reduced myeloperoxidase staining in the infarcted myocardium, decreased apoptosis in cultured cardiomyocytes and fibroblasts, as assessed by Hoechst staining and TUNEL assay, attenuated the accumulation of p53 and phosphorylated p53 and cleaved caspase 3 induced by MI or Ang II, as assessed by Western blotting, and up-regulated growth differentiation factor-15 (GDF-15). In cultured cardiomyocytes and fibroblasts, treatment with Ang II, Aldo or anoxia significantly down-regulated the expression of GDF-15.
  
  
  CONCLUSIONS
  Olm 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 AT1 receptor anatagonist to patients with acute MI is a potential preventive approach for cardiac rupture.
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Guangzhou, China.
authors.forename: Baihe
authors.initials: B
authors.lastname: Chen
authors.forename: Di
authors.initials: D
authors.lastname: Lu
authors.forename: Yujuan
authors.initials: Y
authors.lastname: Fu
authors.forename: Jingwen
authors.initials: J
authors.lastname: Zhang
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Huang
authors.forename: Shiping
authors.initials: S
authors.lastname: Cao
authors.forename: Dingli
authors.initials: D
authors.lastname: Xu
authors.forename: Jianping
authors.initials: J
authors.lastname: Bin
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kitakaze
authors.forename: Qiaobing
authors.initials: Q
authors.lastname: Huang
authors.forename: Yulin
authors.initials: Y
authors.lastname: Liao
mesh_terms: D000450:Aldosterone / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D055436:Growth Differentiation Factor 15 / Q000378:metabolism*; D006341:Heart Rupture / Q000378:metabolism / Q000517:prevention & control*; D000860:Hypoxia / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; C526141:Gdf15 protein, mouse; D055436:Growth Differentiation Factor 15; D007093:Imidazoles; D013777:Tetrazoles; D016159:Tumor Suppressor Protein p53; D000804:Angiotensin II; D000450:Aldosterone; C437965:olmesartan; D009195:Peroxidase
keywords: GDF-15; aldosterone; cardiac rupture; myocardial infarction; olmesartan; p53
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