TFEB insufficiency promotes cardiac hypertrophy by blocking autophagic degradation of GATA4.
TFEB insufficiency promotes cardiac hypertrophy by blocking autophagic degradation of GATA4.
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TFEB 不足通过阻止 GATA4 的自噬降解促进心脏肥大
DOI：
10.1016/j.jbc.2021.101189
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Liu J
中科院分区：
文献类型：
--
作者：
Song R;Lei H;Feng L;Cheng W;Li Y;Yao LL;Liu J
自噬体-溶酶体途径（ALP）不足被认为在心肌肥厚的发病机制中起关键作用。然而，ALP功能不全的机制在很大程度上仍然未知，并且缺乏特异性操纵ALP功能不全治疗心脏肥厚的策略。转录因子EB （Transcription factor EB， TFEB）作为ALP的主调控因子，调控自噬体和溶酶体的生成和功能。我们发现扩张型心肌病患者的TFEB显著降低，而自噬体标志物在苯肾上腺素（PE）诱导的和横向主动脉收缩诱导的心肌细胞肥大和心力衰竭中升高。抑制TFEB诱导ALP功能不全，表现为自噬体标志物增加，轻链3II通量降低，心房钠肽和β-肌球蛋白重链水平升高，细胞大小增大，心肌细胞肥大。TFEB下调的影响通过促进自噬而被消除。TFEB过表达可改善自噬通量，减轻pe刺激的心肌细胞肥大和横断主动脉收缩引起的肥厚重塑、纤维化和心功能障碍。姜黄素类似物C1，一种特定的TFEB激活剂，类似地减轻pe诱导的ALP不全和心肌细胞肥大。TFEB敲低增加了GATA4的积累，GATA4是几种基因的转录因子，通过阻断GATA4的自噬降解导致心脏肥厚，而敲低GATA4可减轻TFEB下调诱导的心肌细胞肥厚。TFEB过表达和C1均可促进GATA4的自噬降解，减轻pe诱导的心肌细胞肥大。综上所述，TFEB下调通过引起ALP功能不全和阻断自噬降解，在压力超负荷引起的心肌肥厚的发展中起着至关重要的作用。激活TFEB是治疗心肌肥厚的一种潜在的治疗策略。
Autophagosome–lysosome pathway (ALP) insufficiency has been suggested to play a critical role in the pathogenesis of cardiac hypertrophy. However, the mechanisms underlying ALP insufficiency remain largely unknown, and strategies to specifically manipulate ALP insufficiency for treating cardiac hypertrophy are lacking. Transcription factor EB (TFEB), as a master regulator of ALP, regulates the generation and function of autophagosomes and lysosomes. We found that TFEB was significantly decreased, whereas autophagosome markers were increased in phenylephrine (PE)-induced and transverse aortic constriction–induced cardiomyocyte hypertrophy and failing hearts from patients with dilated cardiomyopathy. Knocking down TFEB induced ALP insufficiency, as indicated by increased autophagosome markers, decreased light chain 3II flux, and cardiomyocyte hypertrophy manifested through increased levels of atrial natriuretic peptide and β-myosin heavy chain and enlarged cell size. The effects of TFEB knockdown were abolished by promoting autophagy. TFEB overexpression improved autophagic flux and attenuated PE-stimulated cardiomyocyte hypertrophy and transverse aortic constriction–induced hypertrophic remodeling, fibrosis, and cardiac dysfunction. Curcumin analog compound C1, a specific TFEB activator, similarly attenuated PE-induced ALP insufficiency and cardiomyocyte hypertrophy. TFEB knockdown increased the accumulation of GATA4, a transcription factor for several genes causing cardiac hypertrophy by blocking autophagic degradation of GATA4, whereas knocking down GATA4 attenuated TFEB downregulation–induced cardiomyocyte hypertrophy. Both TFEB overexpression and C1 promoted GATA4 autophagic degradation and alleviated PE-induced cardiomyocyte hypertrophy. In conclusion, TFEB downregulation plays a vital role in the development of pressure overload–induced cardiac hypertrophy by causing ALP insufficiency and blocking autophagic degradation. Activation of TFEB represents a potential therapeutic strategy for treating cardiac hypertrophy.
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影响因子：
3.9
作者：
Liu, Shenglan;Chen, Shaorui;Jiang, Jianmin
通讯作者：
Jiang, Jianmin
主自噬调节剂TFEB的基因转移导致毒性蛋白质的清除和抗甲型抗肌蛋白缺乏症中肝病的校正。
影响因子：
11.1
作者：
Pastore, Nunzia;Blomenkamp, Keith;Annunziata, Fabio;Piccolo, Pasquale;Mithbaokar, Pratibha;Sepe, Rosa Maria;Vetrini, Francesco;Palmer, Donna;Ng, Philip;Polishchuk, Elena;Iacobacci, Simona;Polishchuk, Roman;Teckman, Jeffrey;Ballabio, Andrea;Brunetti-Pierri, Nicola
通讯作者：
Brunetti-Pierri, Nicola
影响因子：
20.1
作者：
Oka, T;Maillet, M;Molkentin, JD
通讯作者：
Molkentin, JD
DOI：
10.1073/pnas.1305623110
发表时间：
2013-05-07
影响因子：
11.1
作者：
Decressac, Mickael;Mattsson, Bengt;Bjorklund, Anders
通讯作者：
Bjorklund, Anders
影响因子：
4.8
作者：
Liang, QR;De Windt, LJ;Molkentin, JD
通讯作者：
Molkentin, JD