Bcl-2-associated athanogene 3 (BAG3) is a member of a conserved family of cyto-protective molecular co- chaperones. A genome-wide association study, involving multiple families with heart failure due to dilated cardiomyopathy (DCM), identified associated mutations in BAG3. In the same study, analysis of a large four- generation family identified a single amino acid substitution of glutamic acid 455 to lysine (E455K) in BAG3 as the unequivocal cause of DCM. Several other human genetic studies have also identified other mutations in BAG3 that are associated with skeletal and cardiac myopathies. Two independent groups have reported that mice global null for BAG3 exhibit impaired postnatal growth and early lethality at 3-4 weeks. One group reported skeletal myopathy with disrupted Z-disks, characterized by non-inflammatory myofibrillar degeneration with apoptotic features in the knockout mice. The other group reported no prominent apoptosis in these mice but thick and disrupted Z-disks in skeletal muscle. Premature lethality of these mice prevented study of the role of BAG3 in adult heart function. In addition, little is known as to specific roles of the co-chaperone protein BAG3 in cardiomyocytes, or mechanisms by which the BAG3 E455K missense mutation leads to the progression of cardiomyopathy. To address these issues, we have generated BAG3 global and cardiac- specific knockout, and BAG3 E455K knock-in mouse models. Our preliminary data revealed that cardiac- specific knockout of BAG3 results in DCM. Intriguingly, the heat shock protein (HSP), HSPB8, a known partner of BAG3, is dramatically down regulated in hearts of cardiac-specific BAG3 mutants. Homozygous BAG3 E455K mutant mice have a lethal phenotype, similar to that of BAG3 global knockout mice. We have also found that E455K mutant BAG3 protein has lost the ability to interact with HSP70. Taken together, the foregoing observations indicate that BAG3 and its associated chaperone complex play key roles in maintaining normal cardiomyocyte and whole heart function. Accordingly, our hypothesis is that BAG3 plays an essential role in cardiomyocyte protein homeostasis and cardiac function by forming a complex with chaperone proteins to regulate protein quality control, and that the E455K mutation in BAG3 impairs specific aspects of BAG3 function to lead to cardiomyopathy.
Our Specific Aims are: 1. To characterize the roles of BAG3 in cardiomyocytes by analyzing BAG3 cardiac-specific knockout mice and littermate controls for protein homeostasis, cardiac function, and the progression of DCM; 2. To elucidate mechanisms underlying cardiomyopathy consequent to the E455K mutation of BAG3 by analysis of BAG3 E455K knock-in mice, comparing results with BAG3 global loss-of-function mice; 3. To investigate mechanisms by which the BAG3 E455K mutation impacts human cardiomyocyte function, utilizing gene targeted human embryonic stem cell- derived cardiomyocytes containing BAG3 E455K or BAG3 loss-of-function mutations.

Public Health Relevance

Mutations in Bcl-2-associated athanogene 3 (BAG3) result in dilated cardiomyopathy. However, very little is known as to specific role(s) of BAG3 and its associated molecular chaperone complex in maintaining normal cardiomyocyte and whole heart function. Proposed studies are aimed at understanding the role of BAG3 in cardiomyocyte protein homeostasis and cardiac function, and gaining insight into mechanisms by which mutations in BAG3 cause cardiomyopathy.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Wang, Lan-Hsiang
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
Zip Code
Veevers, Jennifer; Farah, Elie N; Corselli, Mirko et al. (2018) Cell-Surface Marker Signature for Enrichment of Ventricular Cardiomyocytes Derived from Human Embryonic Stem Cells. Stem Cell Reports 11:828-841
Stroud, Matthew J; Fang, Xi; Zhang, Jianlin et al. (2018) Luma is not essential for murine cardiac development and function. Cardiovasc Res 114:378-388
Boogerd, Cornelis J; Zhu, Xiaoming; Aneas, Ivy et al. (2018) Tbx20 Is Required in Mid-Gestation Cardiomyocytes and Plays a Central Role in Atrial Development. Circ Res 123:428-442
Moore-Morris, Thomas; Cattaneo, Paola; Guimarães-Camboa, Nuno et al. (2018) Infarct Fibroblasts Do Not Derive From Bone Marrow Lineages. Circ Res 122:583-590
Stroud, Matthew J; Feng, Wei; Zhang, Jianlin et al. (2017) Nesprin 1?2 is essential for mouse postnatal viability and nuclear positioning in skeletal muscle. J Cell Biol 216:1915-1924
Fang, Xi; Bogomolovas, Julius; Wu, Tongbin et al. (2017) Loss-of-function mutations in co-chaperone BAG3 destabilize small HSPs and cause cardiomyopathy. J Clin Invest 127:3189-3200
Ma, Xiaolong; Chen, Chao; Veevers, Jennifer et al. (2017) CRISPR/Cas9-mediated gene manipulation to create single-amino-acid-substituted and floxed mice with a cloning-free method. Sci Rep 7:42244
Guimarães-Camboa, Nuno; Cattaneo, Paola; Sun, Yunfu et al. (2017) Pericytes of Multiple Organs Do Not Behave as Mesenchymal Stem Cells In Vivo. Cell Stem Cell 20:345-359.e5
Hirai, Maretoshi; Arita, Yoh; McGlade, C Jane et al. (2017) Adaptor proteins NUMB and NUMBL promote cell cycle withdrawal by targeting ERBB2 for degradation. J Clin Invest 127:569-582
Fang, Xi; Stroud, Matthew J; Ouyang, Kunfu et al. (2016) Adipocyte-specific loss of PPAR? attenuates cardiac hypertrophy. JCI Insight 1:e89908

Showing the most recent 10 out of 16 publications