Down-regulation of FKBP12.6 and SERCA2a contributes to acute heart failure in septic shock and is related to an up-regulated endothelin signalling pathway

作者：He Hai Bo; Yu Feng; Dai De Zai^*; Dai Yin

来源：Journal of Pharmacy and Pharmacology, 2007, 59(7): 977-984.

DOI：10.1211/jpp.59.7.0010

Acute heart failure (AHF) critically affects morbidity and mortality in patients suffering from septic shock. It is hypothesized that AHF is linked to down-regulation of FKBP12.6 (calstabin 2) and SERCA2a (sarco/encloplasmic reticulurn Ca2+ ATPase 2a), which may be mediated by an activated endothelin (ET) system in the myocardium. The aim of the study was to test whether an attenuation of septic AHF can be achieved by a novel dual endothelin receptor antagonist, CPU0213, in association with up-regulation of FKBP12.6 and SERCA2a in rats. AHF in septic shock was produced by faeces leak from a surgically punctured caecurn for 72 In in rats. CPU0213 (30 mg kg(-1), s.c., every 12 h, for 3 days) was administered to rats 8 h after the operation. In the untreated model group, survival rate markedly decreased (P<0.01), and the cardiac performance was seriously compromised (P<0.01) relative to control. The AHF was characteristically associated with down-regulated mRNA and protein expressions of FKBP12.6, SERCA2a and PLB (phospholamban). Elevated ET-1 and mRNA abundances of the preproET-1, ECE (endothelin converting enzyme) and ETA and ETB receptors in the left ventricular tissue (P<0.01) were found. All abnormalities were reversed significantly following CPU0213 administration. In conclusion, septic AHF is attributed to down-regulation of FKBP12.6 and SERCA2a, which is related to an activated ET system. An enclothelin receptor antagonism of CPU0213 significantly improves the cardiac performance by blocking both ETA and ETB receptors.

• 出版日期2007-7
• 单位中国药科大学