The transcription factor EB (TFEB) sensitizes the heart to chronic pressure overload

Wundersitz, S.; Pablo Tortola, C.; Schmidt, S.; Oliveira Vidal, R.; Kny, M.; Hahn, A.; Zanders, L.; Katus, H.A.; Sauer, S.; Butter, C.; Luft, F.C.; Müller, O.J.; Fielitz, J.

The transcription factor EB (TFEB) sensitizes the heart to chronic pressure overload

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Item Type:	Article
Title:	The transcription factor EB (TFEB) sensitizes the heart to chronic pressure overload
Creators Name:	Wundersitz, S., Pablo Tortola, C., Schmidt, S., Oliveira Vidal, R., Kny, M., Hahn, A., Zanders, L., Katus, H.A., Sauer, S., Butter, C., Luft, F.C., Müller, O.J. and Fielitz, J.
Abstract:	The transcription factor EB (TFEB) promotes protein degradation by the autophagy and lysosomal pathway (ALP) and overexpression of TFEB was suggested for the treatment of ALP-related diseases that often affect the heart. However, TFEB-mediated ALP induction may perturb cardiac stress response. We used adeno-associated viral vectors type 9 (AAV9) to overexpress TFEB (AAV9-Tfeb) or Luciferase-control (AAV9-Luc) in cardiomyocytes of 12-week-old male mice. Mice were subjected to transverse aortic constriction (TAC, 27G; AAV9-Luc: n = 9; AAV9-Tfeb: n = 14) or sham (AAV9-Luc: n = 9; AAV9-Tfeb: n = 9) surgery for 28 days. Heart morphology, echocardiography, gene expression, and protein levels were monitored. AAV9-Tfeb had no effect on cardiac structure and function in sham animals. TAC resulted in compensated left ventricular hypertrophy in AAV9-Luc mice. AAV9-Tfeb TAC mice showed a reduced LV ejection fraction and increased left ventricular diameters. Morphological, histological, and real-time PCR analyses showed increased heart weights, exaggerated fibrosis, and higher expression of stress markers and remodeling genes in AAV9-Tfeb TAC compared to AAV9-Luc TAC. RNA-sequencing, real-time PCR and Western Blot revealed a stronger ALP activation in the hearts of AAV9-Tfeb TAC mice. Cardiomyocyte-specific TFEB-overexpression promoted ALP gene expression during TAC, which was associated with heart failure. Treatment of ALP-related diseases by overexpression of TFEB warrants careful consideration.
Keywords:	Heart Failure, Left Ventricular Hypertrophy, Transcription Factor EB, Animals, Mice
Source:	International Journal of Molecular Sciences
ISSN:	1422-0067
Publisher:	MDPI
Volume:	23
Number:	11
Page Range:	5943
Date:	25 May 2022
Official Publication:	https://doi.org/10.3390/ijms23115943
PubMed:	View item in PubMed

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