alpha B-crystallin/HSPB2 is critical for hyperactive mTOR-induced cardiomyopathy
alpha B-crystallin/HSPB2 is critical for hyperactive mTOR-induced cardiomyopathy
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α B-晶状体蛋白/HSPB2 对于高活性 mTOR 诱发的心肌病至关重要
DOI：
10.1002/jcp.30465
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发表时间：
2021
影响因子：
5.6
通讯作者：
Hongbing Zhang
中科院分区：
文献类型：
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作者：
Lianmei Wang;Fang Wanng;Kemei Liu;Caifeng Long;Yi Chen;Chunjia Li;Li Li;Fangming Liu;Xinyu Zhang;Yanling Jing;Yanan Wang;Aihua Liang;Hongbing Yan;Hongbing Zhang
尽管雷帕霉素(MTOR)信号的异常机制靶点(MTOR)已知会导致心肌病，但其潜在机制仍鲜为人知。由于结节性硬化症患者的皮质结节和淋巴管肌瘤病中存在αB-晶体蛋白和hspB2的增强，我们揭示了αB-晶体蛋白及其邻近的重复基因hspB2在高活动性心肌病中的作用。心脏Tsc1缺失(T1-hKO)可引起小鼠mTOR激活和心肌病。αB-晶体蛋白和hspB_2在这些小鼠的心脏中呈高表达。αB-晶状体蛋白/hspB2基因敲除可逆转T1-hKO小鼠Tsc1介导的胎儿基因表达缺陷、mTOR激活、线粒体损伤、心肌细胞空泡变性、心肌细胞大小和纤维化。与T1-hKO小鼠相比，这些心脏-TSC1；αB-晶体蛋白；hspB2三重基因敲除小鼠的心功能得到改善，心脏重量/体重比更小，死亡率降低。尽管活化的mTOR抑制了T1-hko小鼠的自噬，但切除αB-晶体蛋白和hspB2并不能恢复t1hko小鼠的自噬。MTOR抑制剂抑制T1-hKO小鼠和大鼠心肌细胞系H9C2中αB-晶体蛋白的表达。饥饿激活了H9C2细胞的自噬，抑制了αB-晶体蛋白的表达。由于抑制自噬使饥饿的H9C2细胞恢复了αB-晶体蛋白的表达，因此自噬是αB-晶体蛋白表达的负调节因子。因此，mTOR通过抑制自噬来刺激αB-晶体蛋白的表达。综上所述，αB-晶体蛋白和hspB2在Tsc1基因敲除相关心肌病中起着关键作用，是过度活跃的mTOR相关心肌病的治疗靶点。
Even though aberrant mechanistic target of rapamycin (mTOR) signaling is known to cause cardiomyopathy, its underlying mechanism remains poorly understood. Because augmentation ofαB‐crystallinandhspB2was presented in the cortical tubers and lymphangioleiomyomatosis of tuberous sclerosis complex patients, we deciphered the role ofαB‐crystallinand its adjacent duplicate gene,hspB2, in hyperactive mTOR‐induced cardiomyopathy. CardiacTsc1deletion (T1‐hKO) caused mouse mTOR activation and cardiomyopathy. Overexpression of αB‐crystallin and hspB2 was presented in the hearts of these mice. Knockout ofαB‐crystallin/hspB2reversed deficientTsc1‐mediated fetal gene expression, mTOR activation, mitochondrial damage, cardiomyocyte vacuolar degeneration, cardiomyocyte size, and fibrosis ofT1‐hKO mice. These cardiac‐Tsc1;αB‐crystallin;hspB2triple knockout (tKO) mice had improved cardiac function, smaller heart weight to body weight ratio, and reduced lethality compared withT1‐hKO mice. Even though activated mTOR suppressed autophagy inT1‐hKO mice, ablation ofαB‐crystallinandhspB2failed to restore autophagy in tKO mice. mTOR inhibitors suppressed αB‐crystallin expression inT1‐hKO mice and rat cardiomyocyte line H9C2. Starvation of H9C2 cells activated autophagy and suppressed αB‐crystallin expression. Since inhibition of autophagy restored αB‐crystallin expression in starved H9C2 cells, autophagy is a negative regulator of αB‐crystallin expression. mTOR thus stimulates αB‐crystallin expression through suppression of autophagy. In conclusion, αB‐crystallin and hspB2 play a pivotal role inTsc1knockout‐related cardiomyopathy and are therapeutic targets of hyperactive mTOR‐associated cardiomyopathy.