Interleukin-17 upregulation participates in the pathogenesis of heart failure in mice via NF-κB-dependent suppression of SERCA2a and Cav1.2 expression
Interleukin-17 upregulation participates in the pathogenesis of heart failure in mice via NF-κB-dependent suppression of SERCA2a and Cav1.2 expression
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Interleukin-17 上调通过 NF-kappa B 依赖性抑制 SERCA2a 和 Cav1.2 表达参与小鼠心力衰竭的发病机制
DOI：
10.1038/s41401-020-00580-6
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发表时间：
2021-02-15
影响因子：
8.2
通讯作者：
Pan，Zhen-wei
中科院分区：
文献类型：
--
作者：
Xue，Gen-long;Li，De-sheng;Pan，Zhen-wei
白细胞介素17(IL-17)又称IL-17A，是心脏疾病的重要调节因子，但其在钙相关性心功能不全中的作用尚不清楚。因此，我们研究了IL-17对钙离子转运过程的影响及其在心力衰竭发生发展中的作用。小鼠经腹主动脉缩窄(TAC)诱导心力衰竭。与假手术组相比，这些小鼠血浆和心脏组织中IL-17水平显著升高。77例心力衰竭患者血浆IL-17水平显著高于49例非心力衰竭患者，且与心脏射血分数、短轴缩短率呈负相关。IL-17基因敲除小鼠与野生型小鼠相比，分离的心肌细胞缩短明显增加，并伴有钙瞬变幅度显著增加，SERCA2a和Cav1.2表达上调。在培养的乳鼠心肌细胞中，IL-17(0.1，1 ng/mL)可浓度依赖性地抑制钙瞬变的幅度，并降低SERCA2a和Cav1.2的表达。此外，IL-17处理可增加NF-κB亚单位p50和p65的表达，而p50的下调则逆转了IL-17对SERCA2a和Cav1.2表达的抑制作用。在TAC诱导的小鼠心脏中，IL-17基因敲除恢复了SERCA2a和Cav1.2的表达，增加了钙瞬变和细胞缩短的幅度，进而改善了心功能。此外，IL-17基因敲除可通过抑制钙相关信号通路减轻心肌肥厚。综上所述，IL-17的上调通过核因子-κB介导的钙离子转运和心脏重塑障碍来损害心脏功能。抑制IL-17是治疗心力衰竭的一种潜在的治疗策略。
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.