Author + information
- Received August 1, 2017
- Revision received September 15, 2017
- Accepted September 19, 2017
- Published online February 26, 2018.
- Valerie D. Myers, MSa,
- Joseph M. McClung, PhDb,
- JuFang Wang, MDc,
- Farzaneh G. Tahrir, PhDd,
- Manish K. Gupta, PhDd,
- Jennifer Gordon, PhDd,
- Christopher H. Kontos, MDe,
- Kamel Khalili, PhDd,
- Joseph Y. Cheung, MD, PhDa,c and
- Arthur M. Feldman, MD, PhDa,∗ ()
- aDepartment of Medicine, Division of Cardiology, Lewis Katz School of Medicine, Philadelphia, Pennsylvania
- bDepartment of Physiology, Brody School of Medicine, East Carolina University, Greenville, North Carolina
- cCenter for Translational Medicine, Lewis Katz School of Medicine, Philadelphia, Pennsylvania
- dDepartment of Neuroscience, Lewis Katz School of Medicine, Philadelphia, Pennsylvania
- eDepartment of Medicine, Division of Cardiology, Duke University School of Medicine, Durham, North Carolina
- ↵∗Address for correspondence:
Dr. Arthur M. Feldman, Division of Cardiology, Department of Medicine, Lewis Katz School of Medicine at Temple University, 3401 North Broad Street, Philadelphia, Pennsylvania 19170.
The B-cell lymphoma 2–associated anthanogene (BAG3) protein is expressed most prominently in the heart, the skeletal muscle, and in many forms of cancer. In the heart, it serves as a co-chaperone with heat shock proteins in facilitating autophagy; binds to B-cell lymphoma 2, resulting in inhibition of apoptosis; attaches actin to the Z disk, providing structural support for the sarcomere; and links the α-adrenergic receptor with the L-type Ca2+ channel. When BAG3 is overexpressed in cancer cells, it facilitates prosurvival pathways that lead to insensitivity to chemotherapy, metastasis, cell migration, and invasiveness. In contrast, in the heart, mutations in BAG3 have been associated with a variety of phenotypes, including both hypertrophic/restrictive and dilated cardiomyopathy. In murine skeletal muscle and vasculature, a mutation in BAG3 leads to critical limb ischemia after femoral artery ligation. An understanding of the biology of BAG3 is relevant because it may provide a therapeutic target in patients with both cardiac and skeletal muscle disease.
This research was supported in part by the National Institutes of Health. Dr. McClung was supported by grants ROO HL103797 and RO1 HL125696. Dr. Kontos was supported by grants R21 HL118661 and RO1 HL124444. Dr. Feldman was supported by grant PO1 HL 091799-01. Drs. Khalili, Cheung, and Feldman were supported by grant RO1 HL123093 from the National Institutes of Health. Ms. Myers, Dr. Feldman, Dr. McClung, Dr. Kontos, and Dr. Cheung have equity in Renovacor, Inc. Drs. Khalili and Feldman have a pending U.S. patent: 61/934,483, BAG3 as a target for therapy of heart failure. Drs. Cheung and Feldman have a pending U.S. patent: 62/205,990, BAG3 composition and methods. Exclusive rights to the patents have been optioned by Temple University to Renovacor, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received August 1, 2017.
- Revision received September 15, 2017.
- Accepted September 19, 2017.
- 2018 The Authors
- Central Illustration
- What Is B-Cell Lymphoma 2–Associated Athanogene 3?
- BAG3 Protein–Binding Domains Provide Functional Pleiotropy
- BAG3 Plays a Critical Role in Maintaining Cardiac Homeostasis
- BAG3 Is Important in the Pathobiology of Ischemia/Reperfusion Injury
- A Nonsynonymous Mutation in BAG3 Leads to the Development of a Myofibrillar Myopathy
- Mutations in BAG3 Can Lead to a Dilated Cardiomyopathy
- Can Nonsynonymous Single Nucleotide Polymorphisms in BAG3 Cause Dilated Cardiomyopathy?
- BAG3 Mutations May Play a Role in the Occurrence of Takotsubo Cardiomyopathy
- BAG3 Plays a Role in Human Immunodeficiency Virus–Associated Cardiomyopathy
- A BAG3 Variant Is Associated With Critical Limb Ischemia in Mice
- BAG3 Mutations Are a Risk Factor for Myocarditis
- Can BAG3 Serve as a Therapeutic Target in Cardiac and Skeletal Muscle Disease?