MSTN Attenuates Cardiac Hypertrophy through Inhibition of Excessive Cardiac Autophagy by Blocking AMPK/mTOR and miR-128/PPARγ/NF-κB
MSTN Attenuates Cardiac Hypertrophy through Inhibition of Excessive Cardiac Autophagy by Blocking AMPK/mTOR and miR-128/PPARγ/NF-κB
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DOI：
10.1016/j.omtn.2019.12.003
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发表时间：
2020-03-06
影响因子：
8.8
通讯作者：
Sun, Hongli
中科院分区：
文献类型：
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作者：
Qi, Hanping;Ren, Jing;Sun, Hongli
心脏肥厚是心脏对负荷增加的反应，是心力衰竭的主要危险因素。肌生长抑制素（MSTN）是一种肌生成抑制剂，调节骨骼肌细胞的数量和大小。近年来，心肌细胞自噬也被认为参与了肥厚反应的控制。然而，关于MSTN通过调控心肌细胞自噬而影响心肌肥厚的具体机制尚不清楚。在本研究中，我们发现MSTN的缺失增强了腹主动脉缩窄（AAC）和血管紧张素II （Ang II）诱导的病理性心肌肥大和心脏自噬；然而，在体内和体外，MSTN显著降低了AAC和Ang ii诱导的心脏肥大表型和心脏自噬。在机制上，MSTN在病理刺激下介导的抗肥大和抗自噬作用与活化蛋白激酶(AMPK)/哺乳动物雷帕霉素靶点（mTOR）的直接失活和过氧化物酶体增殖体活化受体γ (PPAR γ)/核因子κ B （nf - κ B）信号通路的激活有关。此外，miR-128通过抑制其靶点PPAR γ加重了心肌肥厚的进展。此外，MSTN下调AAC和Ang II诱导的miR-128的表达。综上所述，MSTN通过阻断AMPK/mTOR和miR-128/PPAR γ /NF-kappa B信号通路抑制过度的心脏自噬，至少在一定程度上显著减弱了病理性心脏肥大和功能障碍。
Cardiac hypertrophy, a response of the heart to increased workload, is a major risk factor for heart failure. Myostatin (MSTN) is an inhibitor of myogenesis, regulating the number and size of skeletal myocytes. In recent years, cardiomyocyte autophagy also has been considered to be involved in controlling the hypertrophic response. However, less is known about the detailed mechanism of MSTN on cardiac hypertrophy via regulation of cardiomyocyte autophagy. In this study, we found that the deletion of MSTN potentiated abdominal aorta coarctation (AAC) and angiotensin II (Ang II)-induced pathological cardiac hypertrophy and cardiac autophagy; however, AAC and Ang II-induced cardiac hypertrophic phenotype and cardiac autophagy were dramatically diminished by MSTN in vivo and in vitro. Mechanistically, the anti-hypertrophic and anti-autophagic effects mediated by MSTN in response to pathological stimuli were associated with the direct inactivation of activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) and activation of the peroxisome proliferator-activated receptor gamma (PPAR gamma)/nuclear factor kappa B (NF-kappa B) signaling pathway. Additionally, miR-128 aggravated the progression of cardiac hypertrophy through suppressing its target PPAR gamma. Furthermore, MSTN downregulated miR-128 expression induced by AAC and Ang II. Taken together, MSTN significantly blunts pathological cardiac hypertrophy and dysfunction, at least in part, by inhibiting excessive cardiac autophagy via blocking AMPK/mTOR and miR-128/PPAR gamma/NF-kappa B signaling pathways.