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

Valerie D. Myers, Dhanendra Tomar, Muniswamy Madesh, Ju Fang Wang, Jianliang Song, Xue Qian Zhang, Manish K. Gupta, Farzaneh G. Tahrir, Jennifer Gordon, Joseph M. McClung, Christopher D. Kontos, Kamel Khalili, Joseph Y. Cheung, Arthur M. Feldman

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

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 (BAG3 fl/+ ). 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 −/− BAG3 fl/+ ). 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 ([Ca 2+ ] 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.

Original languageEnglish (US)
Pages (from-to)6319-6326
Number of pages8
JournalJournal of Cellular Physiology
Volume233
Issue number9
DOIs
StatePublished - Sep 2018

Keywords

  • BAG3
  • cardiomyopathy (DCM)
  • genetic mutation
  • haplo-insufficiency

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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