Department of Pathophysiology, Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Shenzhen University Health Science Center, Shenzhen, China; College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen, China.
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
J Biol Chem. 2021 Oct;297(4):101189. doi: 10.1016/j.jbc.2021.101189. Epub 2021 Sep 10.
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.
自噬溶酶体途径（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 不足的机制在很大程度上仍然未知，并且缺乏专门用于治疗心肌肥厚的 ALP 不足的策略。转录因子 EB（TFEB）作为 ALP 的主要调节因子，调节自噬体和溶酶体的生成和功能。我们发现，在去甲肾上腺素（PE）诱导和主动脉缩窄诱导的心肌肥厚以及扩张型心肌病患者的衰竭心脏中，TFEB 显著减少，而自噬体标志物增加。TFEB 的敲低导致 ALP 不足，表现为自噬体标志物增加、LC3II 通量减少以及心房利钠肽和β-肌球蛋白重链水平升高和细胞增大的心肌肥厚。促进自噬可消除 TFEB 敲低的作用。TFEB 的过表达改善了自噬流，并减轻了 PE 刺激的心肌肥厚和主动脉缩窄诱导的肥厚重塑、纤维化和心功能障碍。姜黄素类似物化合物 C1，一种特定的 TFEB 激活剂，同样减轻了 PE 诱导的 ALP 不足和心肌肥厚。TFEB 的敲低增加了 GATA4 的积累，GATA4 是几种导致心肌肥厚的基因的转录因子，通过阻断 GATA4 的自噬降解来引起心肌肥厚，而敲低 GATA4 则减轻了 TFEB 下调诱导的心肌肥厚。TFEB 的过表达和 C1 均促进了 GATA4 的自噬降解并缓解了 PE 诱导的心肌肥厚。总之，TFEB 的下调通过引起 ALP 不足和阻断自噬降解在压力超负荷诱导的心肌肥厚的发展中起重要作用。TFEB 的激活代表了治疗心肌肥厚的潜在治疗策略。
