Irisin alleviates pressure overload-induced cardiac hypertrophy by inducing protective autophagy via mTOR-independent activation of the AMPK-ULK1 pathway
Irisin alleviates pressure overload-induced cardiac hypertrophy by inducing protective autophagy via mTOR-independent activation of the AMPK-ULK1 pathway
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Irisin 通过 AMPK-ULK1 通路的 mTOR 独立激活诱导保护性自噬，从而减轻压力超载引起的心脏肥大
DOI：
10.1016/j.yjmcc.2018.07.250
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发表时间：
2018-08-01
影响因子：
5
通讯作者：
Jiang, Wei
中科院分区：
文献类型：
--
作者：
Li, Ru-Li;Wu, Si-Si;Jiang, Wei
在肥大的心脏中，自噬流量不足被认为是导致适应不良的心脏重构和心力衰竭的关键病理。本研究旨在阐明一种新的心肌细胞因子和脂肪细胞因子Irisin在心肌肥厚和重构中的作用及其机制。成年雄性野生型、小鼠-FNDC 5（鸢尾素-前体）-敲除和FNDC 5转基因小鼠单独接受4周的横向主动脉缩窄（TAC）或与腹膜内注射二磷酸氯喹（CQ）组合。内源性FNDC 5消融加重和外源性FNDC 5过表达减轻TAC诱导的心肌肥厚损伤，这与鸢尾素对血管紧张素II（Ang II）或苯肾上腺素（PE）诱导的心肌细胞肥大的保护作用相当。TAC处理的心肌和Ang II或PE损伤的心肌细胞中发生了累积的自噬体和受损的自噬通量。Irisin缺乏导致自噬减少和加重自噬通量失败，而Irisin过表达或补充诱导保护性自噬和改善自噬通量，这被自噬抑制剂Atg 5 siRNA、3-MA和CQ逆转。Irisin在肥厚心肌和培养的心肌细胞中仅增强AMPK的活性，而不增强Akt和MAPK家族成员的活性，并进一步激活Ser 555的ULK 1，而不激活Ser 757，并且不影响mTOR-S6 K轴。分别用化合物C和SBI-0206965阻断AMPK和ULK 1，都废除了鸢尾素对心肌细胞肥大性损伤的保护，并逆转了其对自噬和自噬通量的诱导。我们的研究结果表明，鸢尾素通过激活AMPK-ULK 1信号转导诱导保护性自噬和自噬通量来保护压力超负荷诱导的心脏肥大。
In hypertrophic hearts, autophagic flux insufficiency is recognized as a key pathology leading to maladaptive cardiac remodeling and heart failure. This study aimed to illuminate the cardioprotective role and mechanisms of a new myokine and adipokine, irisin, in cardiac hypertrophy and remodeling. Adult male wild-type, mouse-FNDC5 (irisin-precursor)-knockout and FNDC5 transgenic mice received 4 weeks of transverse aortic constriction (TAC) alone or combined with intraperitoneal injection of chloroquine diphosphate (CQ). Endogenous FNDC5 ablation aggravated and exogenous FNDC5 overexpression attenuated the TAC-induced hypertrophic damage in the heart, which was comparable to the protection of irisin against cardiomyocyte hypertrophy induced by angiotensin II (Ang II) or phenylephrine (PE). Accumulated autophagosome and impaired autophagy flux occurred in the TAC-treated myocardium and Ang II- or PE-insulted cardiomyocytes. Irisin deficiency caused reduced autophagy and aggravated autophagy flux failure, whereas irisin overexpression or supplementation induced protective autophagy and improved autophagy flux, which were reversed by autophagy inhibitors Atg5 siRNA, 3-MA and CQ. Irisin boosted the activity of only AMPK but not Akt and MAPK family members in hypertrophic hearts and cultured cardiomyocytes and further activated ULK1 at Ser555 but not Ser757 and did not affect the mTOR-S6K axis. Blockage of AMPK and ULK1 with compund C and SBI-0206965, respectively, both abrogated irisin's protection against cardiomyocyte hypertrophic injury and reversed its induction of both autophagy and autophagy flux. Our results suggest that irisin protects against pressure overload-induced cardiac hypertrophy by inducing protective autophagy and autophagy flux via activating AMPK-ULK1 signaling.