1. TFEB insufficiency promotes cardiac hypertrophy by blocking autophagic degradation of GATA4
- Author
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Rui Song, Han Lei, Wanwen Cheng, Ling Ling Yao, Li Feng, Jie Liu, and Ying Li
- Subjects
Autophagosome ,TF, transcription factor ,LVIDd, diastolic LV internal dimension ,CQ, chloroquine ,ATG7, autophagy-related protein 7 ,mTORC1 ,HF, heart failure ,Biochemistry ,Muscle hypertrophy ,Mice ,RFP, red fluorescent protein ,AAV, adeno-associated virus ,Medicine ,Myocytes, Cardiac ,TFEB, transcription factor EB ,MOI, multiplicity of infection ,FS, fractional shortening ,Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ,BW, body weight ,BafA1, bafilomycin A1 ,IP, immunoprecipitation ,mTORC1, mechanistic target of rapamycin kinase complex 1 ,NPPB, natriuretic peptide precursor B ,Cell biology ,LVIDs, systolic LV internal dimension ,cardiovascular system ,β-MHC, myosin heavy chain-β ,TAC, transverse aortic constriction ,hypertrophy ,Research Article ,autophagy ,NRVM, neonatal rat ventricular myocyte ,WGA, wheat germ agglutinin ,Cardiomegaly ,NIH, the National Institutes of Health ,heart ,MYH7B, myosin heavy chain 7B ,ALP, autophagosome–lysosome pathway ,GATA4 ,Downregulation and upregulation ,Animals ,Humans ,EF, ejection fraction ,PO, pressure overload ,Autophagy-Related Protein 7 ,ANP, atrial natriuretic peptide ,LV, left ventricular ,Molecular Biology ,PGC1α, peroxisome proliferator–activated receptor-gamma coactivator-1α ,KD, knockdown ,Pressure overload ,TFEB ,PE, phenylephrine ,autophagosome–lysosome pathway ,business.industry ,Autophagy ,Cell Biology ,NPPA, natriuretic peptide precursor A ,GATA4 Transcription Factor ,LC3, light chain 3 ,Proteolysis ,business - Abstract
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.
- Published
- 2021