FNDC5/Irisin inhibits pathological cardiac hypertrophy
FNDC5/Irisin inhibits pathological cardiac hypertrophy
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FNDC5/Irisin 抑制病理性心脏肥大
DOI：
10.1042/cs20190016
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发表时间：
2019
期刊：
影响因子：
6
通讯作者：
Peng Wenhui
中科院分区：
文献类型：
--
作者：
Yu Qing;Kou Wenxin;Xu Xu;Zhou Shunping;Luan Peipei;Xu Xiaopeng;Li Hailing;Zhuang Jianhui;Wang Jun;Zhao Yifan;Xu Yawei;Peng Wenhui
心肌肥厚是多种心血管疾病共同的病理生理过程，目前尚无有效的治疗方法。鸢尾素是一种新的肌细胞因子，主要由骨骼肌分泌，被认为参与能量代谢的调节。在本研究中，我们发现，鸢尾素的表达升高，在肥大的小鼠心脏和血清。此外，血管紧张素II诱导的心肌细胞肥大在鸢尾素给药后减弱，在体外鸢尾素敲除后加重。接下来，我们建立了横主动脉缩窄（TAC）诱导的心脏肥大小鼠模型，发现心脏肥大和纤维化显着减弱，心脏功能改善，通过超声心动图评估鸢尾素治疗后。从机制上讲，我们证明了FNDC 5至少部分地以去整合素和金属蛋白酶（ADAM）家族依赖性方式裂解为鸢尾素。ADAM 10是负责切割的候选酶。此外，我们发现鸢尾素处理激活AMPK，随后抑制mTOR的激活。AMPK抑制消除了Irisin给药的保护作用。综上所述，我们发现鸢尾素以ADAM家族依赖的方式分泌，鸢尾素治疗主要通过调节AMPK-mTOR信号通路改善心功能，减轻压力超负荷诱导的心脏肥大和纤维化。
Cardiac hypertrophy is a common pathophysiological process in various cardiovascular diseases, which still has no effective therapies. Irisin is a novel myokine mainly secreted by skeletal muscle and is believed to be involved in the regulation of energy metabolism. In the present study, we found that irisin expression was elevated in hypertrophic murine hearts and serum. Moreover, angiotension II-induced cardiomyocyte hypertrophy was attenuated after irisin administration and aggravated after irisin knockdownin vitro. Next, we generated transverse aortic constriction (TAC)-induced cardiac hypertrophy murine model and found that cardiac hypertrophy and fibrosis were significantly attenuated with improved cardiac function assessed by echocardiography after irisin treatment. Mechanistically, we demonstrated that FNDC5 was cleaved into irisin, at least partially, in a disintegrin and metalloproteinase (ADAM) family-dependent manner. ADAM10 was the candidate enzyme responsible for the cleavage. Further, we found irisin treatment activated AMPK and subsequently inhibited activation of mTOR. AMPK inhibition ablated the protective role of irisin administration. In conclusion, we find irisin is secreted in an ADAM family-dependent manner, and irisin treatment improves cardiac function and attenuates pressure overload-induced cardiac hypertrophy and fibrosis mainly through regulating AMPK-mTOR signaling.