Interleukin-17 upregulation participates in the pathogenesis of heart failure in mice via NF-κB-dependent suppression of SERCA2a and Cav1.2 expression

• 作者: Gen-long Xue De-sheng Li Zhi-yong Wang Yang Liu Ji-ming Yang Chang-zhu Li Xing-da Li Jiu-dong Ma Man-man Zhang Yan-jie Lu Yue Li Bao-feng Yang Zhen-wei Pan
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2021,（11）
• 所属期刊栏目: Cardiovascular Pharmacology
• 页码范围: 1780-1789
• 页数: 10页
• 语种: 英文

摘要

Interleukin-17 (IL-17),also called IL-17A,is an important regulator of cardiac diseases,but its role in calcium-related cardiac dysfunction remains to be explored.Thus,we investigated the influence of IL-17 on calcium handling process and its contribution to the development of heart failure.Mice were subjected to transaortic constriction (TAC) to induce heart failure.In these mice,the levels of IL-17 in the plasma and cardiac tissue were significantly increased compared with the sham group.In 77 heart failure patients,the plasma level of IL-17 was significantly higher than 49 non-failing subjects,and was negatively correlated with cardiac ejection fraction and fractional shortening.In IL-17 knockout mice,the shortening of isolated ventricular myocytes was increased compared with that in wild-type mice,which was accompanied by significantly increased amplitude of calcium transient and the upregulation of SERCA2a and Cav1.2.In cultured neonatal cardiac myocytes,treatment of with IL-17 (0.1,1 ng/mL) concentration-dependently suppressed the amplitude of calcium transient and reduced the expression of SERCA2a and Cav1.2.Furthermore,IL-17 treatment increased the expression of the NF-KB subunits p50 and p65,whereas knockdown of p50 reversed the inhibitory effects of IL-17 on SERCA2a and Cav1.2 expression.In mice with TAC-induced mouse heart,IL-17 knockout restored the expression of SERCA2a and Cav1.2,increased the amplitude of calcium transient and cell shortening,and in turn improved cardiac function.In addition,IL-17 knockout attenuated cardiac hypertrophy with inhibition of calcium-related signaling pathway.In conclusion,upregulation of IL-17 impairs cardiac function through NF-κB-mediated disturbance of calcium handling and cardiac remodeling.Inhibition of IL-17 represents a potential therapeutic strategy for the treatment of heart failure.