Abstract
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-κB 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.
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Acknowledgements
This work was supported by National Key R&D Program of China (2017YFC1307404 to ZWP), National Natural Science Foundation of China (81730012 to BFY and 81870295 to ZWP), Funds for Distinguished Young Scholars of Heilongjiang Province (to ZP), Heilongjiang Touyan Innovation Team Program (to BFY) and Yu Weihan Excellent Youth Foundation of Harbin Medical University (001000004 to ZWP).
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GLX and DSL performed experiments, analyzed data, and prepared the paper. ZYW, YL, JMY, CZL, XDL, JDM, MMZ, YJL and YL helped perform experiments and collect data. BFY and ZWP designed the project, oversaw the experiments and prepared the paper.
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Xue, Gl., Li, Ds., Wang, Zy. et al. Interleukin-17 upregulation participates in the pathogenesis of heart failure in mice via NF-κB-dependent suppression of SERCA2a and Cav1.2 expression. Acta Pharmacol Sin 42, 1780–1789 (2021). https://doi.org/10.1038/s41401-020-00580-6
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DOI: https://doi.org/10.1038/s41401-020-00580-6
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