Haplo-insufficiency of Bcl2-associated Athanogene 3 in Mice Results in Progressive Left Ventricular Dysfunction, β-Adrenergic Insensitivity and Increased Apoptosis

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 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.