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TFEB insufficiency promotes cardiac hypertrophy by blocking autophagic degradation of GATA4
- Source :
- The Journal of Biological Chemistry
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
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.
- 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
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 297
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....f8c5ade638442a6ab31fc6f569d9e71c