Simvastatin and rosuvastatin attenuate necroptosis in rat failing hearts following myocardial infarction; the contribution of Hsp90 inhibition in cardiomyocytes to prevent necroptosis.

Statins, a class of dyslipidemic drugs known as HMG-CoA reductase inhibitors, have emerged as promising compounds for the treatment of chronic heart failure. Nevertheless, the precise mechanism remains to be fully elucidated. Necroptosis is a programmed necrosis-like cell death and has been involved in the development of chronic heart failure. However, it is unclear whether statins exert beneficial effects on therapy for heart failure by inhibiting cardiomyocyte necroptosis. In this study, we administered statins to rats after myocardial infarction and evaluated their effects on the necroptosis pathway in the failing heart following myocardial infarction. Administration of simvastatin or rosuvastatin reduced cardiac dysfunction after myocardial infarction. Concomitantly, the statins prevented the activation of the necroptotic intracellular signaling pathway in myocardial tissue. Simvastatin, but not rosuvastatin treatment attenuated the interaction between Hsp90 and necroptosis-related proteins in myocardial tissue, suggesting that simvastatin prevents necroptosis via Hsp90 inhibition. Necroptosis induced in primary cultured cardiomyocytes isolated from neonatal rats was inhibited by pretreatment with simvastatin. Administration of simvastatin and rosuvastatin inhibited the infiltration of M1 macrophages into myocardial tissue and reduced the myocardial tissue content of tumor necrosis factor-α, an inflammatory cytokine that induces necroptosis, respectively. The findings in the study indicate that statins may prevent necroptosis of cardiomyocytes, attenuating the development of heart failure. However, the present study suggests that the cardioprotective mechanism of simvastatin is not same as that of rosuvastatin.