Abstract 16634: Bcl2 Associated Athanogene 3 Haplo-insufficiency Decreases Cardiac Function and Attenuates Response to Stress

Bcl2-associated athanogene 3 (BAG3) is a 575 amino acid protein found in the heart, skeletal muscle and many cancer cell types. In the heart, it inhibits apoptosis and enhances autophagy while facilitating excitation-contraction coupling. Patients with deletions or truncations of BAG3 have haplo-insufficency. We made a haplo-insufficient mouse model by flanking an allele of BAG3 with loxP recombination sites (BAG3fl/+). BAG3fl/+ crossed with α-MHC-Cre mice generated cardiac specific BAG3 haplo-insufficient mice (cBAG3+/-). We used echocardiography to assess the cardiac phenotype. At 12 weeks of age, cardiac myocytes were isolated and examined for contractile force, calcium transient [Ca]i amplitude and mitochondrial membrane potential. Compared with Cre-/-BAG3fl/+ littermates (control), heart size and left ventricular ejection fraction (LVEF) in cBAG3+/- mice were unchanged at 8 weeks of age despite a 50% decrease in cardiac BAG3 but by 12 weeks LVEF has declined in males but not in females (Fig 1A & B). ...