Haplo-insufficiency of Bcl2-associated athanogene 3 in mice results in progressive left ventricular dysfunction, β-adrenergic insensitivity, and increased apoptosis.

Published

Journal Article

Bcl2-associated athanogene 3 (BAG3) is a 575 amino acid protein that is found predominantly in the heart, skeletal muscle, and many cancers. Deletions and truncations in BAG3 that result in haplo-insufficiency have been associated with the development of dilated cardiomyopathy. To study the cellular and molecular events attributable to BAG3 haplo-insufficiency we generated a mouse in which one allele of BAG3 was flanked by loxP recombination sites (BAG3fl/+ ). Mice were crossed with α-MHC-Cre mice in order to generate mice with cardiac-specific haplo-insufficiency (cBAG3+/-) and underwent bi-weekly echocardiography to assess their cardiac phenotype. By 10 weeks of age, cBAG3+/- mice demonstrated increased heart size and diminished left ventricular ejection fraction when compared with non-transgenic littermates (Cre-/- BAG3fl/+ ). Contractility in adult myocytes isolated from cBAG3+/- mice were similar to those isolated from control mice at baseline, but showed a significantly decreased response to adrenergic stimulation. Intracellular calcium ([Ca2+ ]i ) transient amplitudes in myocytes isolated from cBAG3+/- mice were also similar to myocytes isolated from control mice at baseline but were significantly lower than myocytes from control mice in their response to isoproterenol. BAG3 haplo-insufficiency was also associated with decreased autophagy flux and increased apoptosis. Taken together, these results suggest that mice in which BAG3 has been deleted from a single allele provide a model that mirrors the biology seen in patients with heart failure and BAG3 haplo-insufficiency.

Full Text

Duke Authors

Cited Authors

  • Myers, VD; Tomar, D; Madesh, M; Wang, J; Song, J; Zhang, X-Q; Gupta, MK; Tahrir, FG; Gordon, J; McClung, JM; Kontos, CD; Khalili, K; Cheung, JY; Feldman, AM

Published Date

  • September 2018

Published In

Volume / Issue

  • 233 / 9

Start / End Page

  • 6319 - 6326

PubMed ID

  • 29323723

Pubmed Central ID

  • 29323723

Electronic International Standard Serial Number (EISSN)

  • 1097-4652

Digital Object Identifier (DOI)

  • 10.1002/jcp.26482

Language

  • eng

Conference Location

  • United States