ATF6 protects against protein misfolding during cardiac hypertrophy.

Autor: Hofmann C; Department of Internal Medicine III (Cardiology, Angiology, and Pneumology), Heidelberg University Hospital, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany; SDSU Heart Institute and Department of Biology, San Diego State University, San Diego, CA, USA., Aghajani M; Department of Internal Medicine and the Translational Cardiovascular Research Center, University of Arizona College of Medicine - Phoenix, Phoenix, USA., Alcock CD; Department of Internal Medicine and the Translational Cardiovascular Research Center, University of Arizona College of Medicine - Phoenix, Phoenix, USA., Blackwood EA; Department of Internal Medicine and the Translational Cardiovascular Research Center, University of Arizona College of Medicine - Phoenix, Phoenix, USA., Sandmann C; Department of Internal Medicine III (Cardiology, Angiology, and Pneumology), Heidelberg University Hospital, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany., Herzog N; Department of Internal Medicine III (Cardiology, Angiology, and Pneumology), Heidelberg University Hospital, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany., Groß J; Department of Internal Medicine III (Cardiology, Angiology, and Pneumology), Heidelberg University Hospital, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany., Plate L; Department of Chemistry, Vanderbilt University, Nashville, TN, USA; Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA., Wiseman RL; Department of Molecular Medicine, Scripps Research, La Jolla, CA, USA., Kaufman RJ; Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Katus HA; Department of Internal Medicine III (Cardiology, Angiology, and Pneumology), Heidelberg University Hospital, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany., Jakobi T; Department of Internal Medicine III (Cardiology, Angiology, and Pneumology), Heidelberg University Hospital, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany; Department of Internal Medicine and the Translational Cardiovascular Research Center, University of Arizona College of Medicine - Phoenix, Phoenix, USA., Völkers M; Department of Internal Medicine III (Cardiology, Angiology, and Pneumology), Heidelberg University Hospital, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany., Glembotski CC; Department of Internal Medicine and the Translational Cardiovascular Research Center, University of Arizona College of Medicine - Phoenix, Phoenix, USA., Doroudgar S; Department of Internal Medicine III (Cardiology, Angiology, and Pneumology), Heidelberg University Hospital, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany; Department of Internal Medicine and the Translational Cardiovascular Research Center, University of Arizona College of Medicine - Phoenix, Phoenix, USA. Electronic address: sdoroudgar@arizona.edu.
Jazyk: angličtina
Zdroj: Journal of molecular and cellular cardiology [J Mol Cell Cardiol] 2024 Apr; Vol. 189, pp. 12-24. Date of Electronic Publication: 2024 Feb 23.
DOI: 10.1016/j.yjmcc.2024.02.001
Abstrakt: Cardiomyocytes activate the unfolded protein response (UPR) transcription factor ATF6 during pressure overload-induced hypertrophic growth. The UPR is thought to increase ER protein folding capacity and maintain proteostasis. ATF6 deficiency during pressure overload leads to heart failure, suggesting that ATF6 protects against myocardial dysfunction by preventing protein misfolding. However, conclusive evidence that ATF6 prevents toxic protein misfolding during cardiac hypertrophy is still pending. Here, we found that activation of the UPR, including ATF6, is a common response to pathological cardiac hypertrophy in mice. ATF6 KO mice failed to induce sufficient levels of UPR target genes in response to chronic isoproterenol infusion or transverse aortic constriction (TAC), resulting in impaired cardiac growth. To investigate the effects of ATF6 on protein folding, the accumulation of poly-ubiquitinated proteins as well as soluble amyloid oligomers were directly quantified in hypertrophied hearts of WT and ATF6 KO mice. Whereas only low levels of protein misfolding was observed in WT hearts after TAC, ATF6 KO mice accumulated increased quantities of misfolded protein, which was associated with impaired myocardial function. Collectively, the data suggest that ATF6 plays a critical adaptive role during cardiac hypertrophy by protecting against protein misfolding.
Competing Interests: Declaration of competing interest The authors declare no conflict of interest.
(Copyright © 2024. Published by Elsevier Ltd.)
Databáze: MEDLINE
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