BGP-15 ameliorates sepsis-induced cardiomyopathy via SIRT3/SOD2-associated antioxidant signaling and suppression of myocardial inflammation.

INTRODUCTION

Sepsis-induced cardiomyopathy is a serious complication of sepsis characterized by acute myocardial dysfunction and substantial mortality. This study evaluated the therapeutic effects of BGP-15 and the potential involvement of SIRT3/SOD2-associated signaling in a mouse model of cecal ligation and puncture (CLP)-induced sepsis.

MATERIALS AND

METHODS

BGP-15 (20 or 40 mg/kg) was administered intravenously once at 6 h after CLP surgery. Survival, cardiac function, myocardial injury, oxidative stress, and inflammatory responses were evaluated. Myocardial SIRT3 expression, SOD2 Lys68 acetylation, and total SOD2 protein were assessed. The SIRT3 inhibitor 3-TYP was co-administered to investigate the potential involvement of SIRT3-related signaling in the effects of BGP-15.

RESULTS

Sepsis was associated with cardiac dysfunction, increased mortality and myocardial injury, reduced myocardial SIRT3 expression, increased SOD2 Lys68 acetylation, and decreased total SOD2 protein. BGP-15 treatment improved survival and cardiac function, reduced serum CK-MB and LDH levels, and attenuated myocardial oxidative and inflammatory injury. High-dose BGP-15 increased SIRT3 expression, both BGP-15 doses reduced the Acetyl-SOD2/SOD2 ratio, and total SOD2 protein was increased. Co-administration of 3-TYP attenuated several cardiac, oxidative, and inflammatory effects associated with BGP-15 treatment, whereas its apparent attenuation of the 14-day survival benefit did not reach statistical significance (log-rank P = 0.1103).

CONCLUSION

These findings support the involvement of SIRT3-related signaling in the cardioprotective effects associated with BGP-15 in experimental sepsis and support further preclinical investigation of BGP-15 for septic cardiomyopathy. SIRT3 and SOD2 enzymatic activities were not measured directly.