Novel BAG3 Variants in African American Patients With Cardiomyopathy: Reduced β-Adrenergic Responsiveness in Excitation-Contraction.

Abstract

BACKGROUND:

We reported 3 novel nonsynonymous single nucleotide variants of Bcl2-associated athanogene 3 (BAG3) in African Americans with heart failure (HF) that are associated with a 2-fold increase in cardiac events (HF hospitalization, heart transplantation, or death).

METHODS AND RESULTS:

We expressed BAG3 variants (P63A, P380S, and A479V) via adenovirus-mediated gene transfer in adult left ventricular myocytes isolated from either wild-type (WT) or cardiac-specific BAG3 haploinsufficient (cBAG3+/-) mice: the latter to simulate the clinical situation in which BAG3 variants are only found on 1 allele. Compared with WT myocytes, cBAG3+/- myocytes expressed approximately 50% of endogenous BAG3 levels and exhibited decreased [Ca2+]i and contraction amplitudes after isoproterenol owing to decreased L-type Ca2+ current. BAG3 repletion with WT BAG3 but not P380S, A479V, or P63A/P380S variants restored contraction amplitudes in cBAG3+/- myocytes to those measured in WT myocytes, suggesting excitation-contraction abnormalities partly account for HF in patients harboring these mutants. Because P63A is near the WW domain (residues 21-55) and A479V is in the BAG domain (residues 420-499), we expressed BAG3 deletion mutants (Δ1-61 and Δ421-575) in WT myocytes and demonstrated that the BAG but not the WW domain was involved in enhancement of excitation-contraction by isoproterenol.

CONCLUSIONS:

The BAG3 variants contribute to HF in African American patients partly by decreasing myocyte excitation-contraction under stress, and that both the BAG and PXXP domains are involved in mediating β-adrenergic responsiveness in myocytes.

• Authors: Arthur M Feldman, Jennifer Gordon, Jufang Wang, Jianliang Song, Xue-Qian Zhang, Valerie D Myers, Dhanendra Tomar, Glenn S Gerhard, Kamel Khalili, Joseph Y Cheung
• Journal: Journal of cardiac failure (J Card Fail) Vol. 26 Issue 12 Pg. 1075-1085 (Dec 2020) ISSN: 1532-8414 [Electronic] United States
• PMID: 32956817 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• Adrenergic Agents
• Apoptosis Regulatory Proteins
• BAG3 protein, human
• Bag3 protein, mouse
• Isoproterenol

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Adrenergic Agents
• Black or African American (genetics)
• Animals
• Apoptosis Regulatory Proteins (metabolism)
• Cardiomyopathies (genetics)
• Heart Failure (genetics)
• Humans
• Isoproterenol (pharmacology)
• Mice
• Myocardial Contraction
• Myocytes, Cardiac (metabolism)