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

Publication ,  Journal Article
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 ...
Published in: J Cell Physiol
September 2018

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.

Duke Scholars

Published In

J Cell Physiol

DOI

EISSN

1097-4652

Publication Date

September 2018

Volume

233

Issue

9

Start / End Page

6319 / 6326

Location

United States

Related Subject Headings

  • Ventricular Dysfunction, Left
  • Receptors, Adrenergic, beta
  • Proto-Oncogene Proteins c-bcl-2
  • Phenotype
  • Myocytes, Cardiac
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Isoproterenol
  • Heart Failure
 

Citation

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Myers, V. D., Tomar, D., Madesh, M., Wang, J., Song, J., Zhang, X.-Q., … Feldman, A. M. (2018). Haplo-insufficiency of Bcl2-associated athanogene 3 in mice results in progressive left ventricular dysfunction, β-adrenergic insensitivity, and increased apoptosis. J Cell Physiol, 233(9), 6319–6326. https://doi.org/10.1002/jcp.26482
Myers, Valerie D., Dhanendra Tomar, Muniswamy Madesh, JuFang Wang, Jianliang Song, Xue-Qian Zhang, Manish K. Gupta, et al. “Haplo-insufficiency of Bcl2-associated athanogene 3 in mice results in progressive left ventricular dysfunction, β-adrenergic insensitivity, and increased apoptosis.J Cell Physiol 233, no. 9 (September 2018): 6319–26. https://doi.org/10.1002/jcp.26482.
Myers, Valerie D., et al. “Haplo-insufficiency of Bcl2-associated athanogene 3 in mice results in progressive left ventricular dysfunction, β-adrenergic insensitivity, and increased apoptosis.J Cell Physiol, vol. 233, no. 9, Sept. 2018, pp. 6319–26. Pubmed, doi:10.1002/jcp.26482.
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. Haplo-insufficiency of Bcl2-associated athanogene 3 in mice results in progressive left ventricular dysfunction, β-adrenergic insensitivity, and increased apoptosis. J Cell Physiol. 2018 Sep;233(9):6319–6326.
Journal cover image

Published In

J Cell Physiol

DOI

EISSN

1097-4652

Publication Date

September 2018

Volume

233

Issue

9

Start / End Page

6319 / 6326

Location

United States

Related Subject Headings

  • Ventricular Dysfunction, Left
  • Receptors, Adrenergic, beta
  • Proto-Oncogene Proteins c-bcl-2
  • Phenotype
  • Myocytes, Cardiac
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Isoproterenol
  • Heart Failure