替米沙坦抑制NLRP3/GSDMD/Caspase-1信号通路改善慢性心衰大鼠心功能

Telmisartan inhibits NLRP3/GSDMD/Caspase-1 signaling pathway to improve cardiac function in chronic heart failure rats

目的基于NOD样受体热蛋白结构域相关蛋白3(NLRP3)/Gasdermin D(GSDMD)/半胱氨酸蛋白酶-1(Caspase-1)信号通路探讨替米沙坦改善慢性心力衰竭的潜在作用机制。方法将40只大鼠随机分为空白对照组、模型组、替米沙坦(30 mg/kg)及MCC950(NLRP3抑制剂,10 mg/kg)组,皮下注射异丙肾上腺素建立慢性心力衰竭大鼠模型。两周后,超声检测大鼠心脏功能;HE染色检测大鼠心肌组织病理变化,Masson染色检测大鼠心肌组织胶原纤维沉积;透射电镜下观察心肌组织超微结构;酶联免疫吸附实验(ELISA)检测各组大鼠血清中白细胞介素-1β(IL-1β)、IL-18表达水平;Western blot方法检测各组大鼠心肌组织中NLRP3、GSDMD、凋亡相关斑点样蛋白(ASC)、pro-caspase-1及Cleaved-caspase-1蛋白表达。结果替米沙坦能显著改善大鼠心脏功能,改善病理损伤,抑制心肌纤维化,显著降低大鼠血清中IL-1β、IL-18表达水平,并显著抑制大鼠心肌组织中NLRP3、GSDMD、ASC、pro-caspase-1及Cleaved-caspase-1蛋白表达。结论替米沙坦能够通过抑制NLRP3/GSDMD/Caspase-1信号通路改善慢性心力衰竭大鼠心功能。

Objective To explore the potential mechanism of telmisartan in improving chronic heart failure based on NOD-like receptor thermal protein domain associated protein 3(NLRP3)/Gasdermin D(GSDMD)/Caspase-1 signaling pathway.Methods 40 rats were randomly divided into control group,model group,Telmisartan(30 mg/kg)and MCC950(NLRP3 inhibitor,10 mg/kg)group.Chronic heart failure rat model was established by subcutaneous injection of isoproterenol.The heart function of rats was measured by ultrasound.The pathological changes of myocardial tissue were detected by HE staining,and the collagen fiber deposition was detected by Masson staining.The ultrastructure of myocardial tissue was observed by transmission electron microscopy.The levels of interleukin-1β(IL-1β)and IL-18 in serum were detected by enzyme-linked immunosorbent assay(ELISA).The expressions of NLRP3,GSDMD,apoptosis-related spot-like protein(ASC),pro-caspase-1 and Cleaved-caspase-1 were detected by Western blot.Results Telmisartan significantly improved cardiac function,ameliorated pathological injury,inhibited myocardial fibrosis,significantly decreased the levels of IL-1βand IL-18 in serum of rats,and significantly inhibited the expressions of NLRP3,GSDMD,ASC,pro-caspase-1 and Cleaved caspase-1 in myocardial tissue of rats.Conclusion Telmisartan can improve cardiac function in rats with chronic heart failure by inhibiting the NLRP3/GSDMD/Caspase-1 signaling pathway.