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Cardiomyocyte-Specific Human Bcl2-Associated Anthanogene 3 P209L Expression Induces Mitochondrial Fragmentation, Bcl2-Associated Anthanogene 3 Haploinsufficiency, and Activates p38 Signaling.

Publication ,  Journal Article
Quintana, MT; Parry, TL; He, J; Yates, CC; Sidorova, TN; Murray, KT; Bain, JR; Newgard, CB; Muehlbauer, MJ; Eaton, SC; Hishiya, A; Takayama, S ...
Published in: Am J Pathol
August 2016

The Bcl2-associated anthanogene (BAG) 3 protein is a member of the BAG family of cochaperones, which supports multiple critical cellular processes, including critical structural roles supporting desmin and interactions with heat shock proteins and ubiquitin ligases intimately involved in protein quality control. The missense mutation P209L in exon 3 results in a primarily cardiac phenotype leading to skeletal muscle and cardiac complications. At least 10 other Bag3 mutations have been reported, nine resulting in a dilated cardiomyopathy for which no specific therapy is available. We generated αMHC-human Bag3 P209L transgenic mice and characterized the progressive cardiac phenotype in vivo to investigate its utility in modeling human disease, understand the underlying molecular mechanisms, and identify potential therapeutic targets. We identified a progressive heart failure by echocardiography and Doppler analysis and the presence of pre-amyloid oligomers at 1 year. Paralleling the pathogenesis of neurodegenerative diseases (eg, Parkinson disease), pre-amyloid oligomers-associated alterations in cardiac mitochondrial dynamics, haploinsufficiency of wild-type BAG3, and activation of p38 signaling were identified. Unexpectedly, increased numbers of activated cardiac fibroblasts were identified in Bag3 P209L Tg+ hearts without increased fibrosis. Together, these findings point to a previously undescribed therapeutic target that may have application to mutation-induced myofibrillar myopathies as well as other common causes of heart failure that commonly harbor misfolded proteins.

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Published In

Am J Pathol

DOI

EISSN

1525-2191

Publication Date

August 2016

Volume

186

Issue

8

Start / End Page

1989 / 2007

Location

United States

Related Subject Headings

  • Real-Time Polymerase Chain Reaction
  • Pathology
  • Myocytes, Cardiac
  • Mutation, Missense
  • Mitochondria
  • Mice, Transgenic
  • Mice
  • MAP Kinase Signaling System
  • In Situ Nick-End Labeling
  • Humans
 

Citation

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Quintana, M. T., Parry, T. L., He, J., Yates, C. C., Sidorova, T. N., Murray, K. T., … Willis, M. S. (2016). Cardiomyocyte-Specific Human Bcl2-Associated Anthanogene 3 P209L Expression Induces Mitochondrial Fragmentation, Bcl2-Associated Anthanogene 3 Haploinsufficiency, and Activates p38 Signaling. Am J Pathol, 186(8), 1989–2007. https://doi.org/10.1016/j.ajpath.2016.03.017
Quintana, Megan T., Traci L. Parry, Jun He, Cecelia C. Yates, Tatiana N. Sidorova, Katherine T. Murray, James R. Bain, et al. “Cardiomyocyte-Specific Human Bcl2-Associated Anthanogene 3 P209L Expression Induces Mitochondrial Fragmentation, Bcl2-Associated Anthanogene 3 Haploinsufficiency, and Activates p38 Signaling.Am J Pathol 186, no. 8 (August 2016): 1989–2007. https://doi.org/10.1016/j.ajpath.2016.03.017.
Quintana, Megan T., et al. “Cardiomyocyte-Specific Human Bcl2-Associated Anthanogene 3 P209L Expression Induces Mitochondrial Fragmentation, Bcl2-Associated Anthanogene 3 Haploinsufficiency, and Activates p38 Signaling.Am J Pathol, vol. 186, no. 8, Aug. 2016, pp. 1989–2007. Pubmed, doi:10.1016/j.ajpath.2016.03.017.
Quintana MT, Parry TL, He J, Yates CC, Sidorova TN, Murray KT, Bain JR, Newgard CB, Muehlbauer MJ, Eaton SC, Hishiya A, Takayama S, Willis MS. Cardiomyocyte-Specific Human Bcl2-Associated Anthanogene 3 P209L Expression Induces Mitochondrial Fragmentation, Bcl2-Associated Anthanogene 3 Haploinsufficiency, and Activates p38 Signaling. Am J Pathol. 2016 Aug;186(8):1989–2007.
Journal cover image

Published In

Am J Pathol

DOI

EISSN

1525-2191

Publication Date

August 2016

Volume

186

Issue

8

Start / End Page

1989 / 2007

Location

United States

Related Subject Headings

  • Real-Time Polymerase Chain Reaction
  • Pathology
  • Myocytes, Cardiac
  • Mutation, Missense
  • Mitochondria
  • Mice, Transgenic
  • Mice
  • MAP Kinase Signaling System
  • In Situ Nick-End Labeling
  • Humans