title: Synergism of simvastatin with losartan prevents angiotensin II-induced cardiomyocyte apoptosis in vitro.
abstract: OBJECTIVE
  Increasing evidence suggests that cardiomyocyte apoptosis has an important role in the transition from compensatory cardiac remodelling to heart failure. The synergistic effect of statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) and angiotensin II (Ang II) type 1 receptor antagonists reduces the incidence of cardiovascular events. However, the anti-apoptotic potential of the synergism between losartan and simvastatin in heart failure remains unexplored. Here, we demonstrate that Ang II-induced apoptosis is prevented by losartan and simvastatin in neonatal cardiomyocytes.
  
  
  METHODS
  The in-vitro cardiomyocyte apoptosis model was established by co-culturing neonate rat cardiomyocytes with Ang II. Cell viability was analysed by the MTT assay. Cell apoptosis was evaluated using fluorescence microscopy and flow cytometry. Apoptosis-related proteins Bax and Bcl-2 expressions were measured by flow cytometry detection.
  
  
  RESULTS
  Incubation with 10(-7) M Ang II for 48 h increased cardiomyocyte apoptosis and decreased cell viability. Losartan (10(-5) M) and simvastatin (10(-5) M), either alone or in combination, significantly decreased Ang II-induced cardiomyocyte apoptosis and increased cell viability. The q values calculated by the probability sum test were 1.31 for cardiomyocyte apoptosis and 1.21 for cell viability. Ang II induced a significant increase in Bax protein expression, whereas Bcl-2 protein expression was decreased. Losartan alone or in combination with simvastatin blocked the increased Bax expression and increased Bcl-2 expression. However, simvastatin had no such effect.
  
  
  CONCLUSIONS
  Our data provide the first evidence that synergism of simvastatin with losartan prevents angiotensin II-induced cardiomyocyte apoptosis in vitro. Synergism between simvastatin and losartan may provide a new therapeutic approach to the prevention of cardiac remodelling.
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.forename: Xiong-Wen
authors.initials: XW
authors.lastname: Lü
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.forename: Peng-Li
authors.initials: PL
authors.lastname: Zhu
authors.forename: Jun
authors.initials: J
authors.lastname: Li
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D019808:Losartan / Q000008:administration & dosage* / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D019821:Simvastatin / Q000008:administration & dosage* / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D000804:Angiotensin II; D019821:Simvastatin; D019808:Losartan