BGP-15 ameliorates sepsis-induced cardiomyopathy via SIRT3/SOD2-associated antioxidant signaling and suppression of myocardial inflammation.
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.
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.
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).
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.
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.
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).
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.
Authors
Zhao Zhao, Liu Liu, Wu Wu, Wang Wang, Ma Ma, Liu Liu, Zheng Zheng, Yang Yang, Zhang Zhang
View on Pubmed