Synergism of simvastatin with losartan prevents angiotensin II-induced cardiomyocyte apoptosis in vitro.
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.
Xu
Jian
J
School of Pharmacy, Anhui Medical University, Hefei, China.
Lü
Xiong-Wen
XW
Huang
Yan
Y
Zhu
Peng-Li
PL
Li
Jun
J
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
D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D000804:Angiotensin II; D019821:Simvastatin; D019808:Losartan