Cardiomyocyte-Specific Human Bcl2-Associated Anthanogene 3 P209L Expression Induces Mitochondrial Fragmentation, Bcl2-Associated Anthanogene 3 Haploinsufficiency, and Activates p38 Signaling.
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.
Department of Surgery, University of North Carolina, Chapel Hill, North Carolina.
Megan T
MT
Quintana
McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina.
Traci L
TL
Parry
General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People's Republic of China.
Jun
J
He
Department of Health Promotions and Development, School of Nursing, University of Pittsburgh, Pittsburgh, Pennsylvania.
Cecelia C
CC
Yates
Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee.
Tatiana N
TN
Sidorova
Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee.
Katherine T
KT
Murray
Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina; Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
James R
JR
Bain
Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina; Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
Christopher B
CB
Newgard
Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina.
Michael J
MJ
Muehlbauer
Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina.
Samuel C
SC
Eaton
Boston Strategics Corp., Boston, Massachusetts.
Akinori
A
Hishiya
Department of Pathology, Boston University, Boston, Massachusetts.
Shin
S
Takayama
McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina; Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina. Electronic address: monte_willis@med.unc.edu.
Monte S
MS
Willis
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D015153:Blotting, Western; D004195:Disease Models, Animal; D004452:Echocardiography; D005455:Fluorescent Antibody Technique; D057895:Haploinsufficiency; D006333:Heart Failure / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000473:pathology; D020125:Mutation, Missense; D032383:Myocytes, Cardiac / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human