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Myers VD, Tomar D, Madesh M, Wang J, Song J, Zhang XQ, 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, beta-Adrenergic Insensitivity and Increased Apoptosis
J Cell Physiol (2018) 233:6319-6326.
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 alpha-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 ten 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. This article is protected by copyright. All rights reserved.
Note
Publication Date: 2018-09-01.
PMCID: PMC5993591
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Last updated on Monday, November 05, 2018