Death‐associated protein kinase mediates myofibril degeneration and myocyte apoptosis induced by beta‐adrenergic receptors (404.3)

Background: In cardiac muscle, persistent stimulation of β‐adrenergic receptors (β‐ARs) and calcium (Ca)2+ signaling plays a central role in regulating contractility, hypertrophy, and apoptosis. The Ca2+/calmodulin‐regulated Serine/Threonine kinase, death‐associated protein kinase (DAPK), regulates cytoskeletal dynamics and cell death. However, the role and activation mechanisms of DAPK in cardiac myocytes and heart failure (HF) are unknown. This study examines the role of DAPK in myocyte death induced by β‐AR stimulation. Methods and Results: We found increased DAPK expression and activation in human failing hearts and in hearts of cardiac‐specific β1‐ARs transgenic mice. This activation of DAPK correlated with myofibril degeneration, myocyte death and cardiac contractile dysfunction, pointing to a possible role of DAPK in the development of HF. We therefore assessed whether DAPK activation was involved in myocyte apoptosis secondary to excess exposure of catecholamine. Chronic treatment with β1‐AR agonist or adenoviral expression of β1‐ARs induced DAPK activation, which was dependent on intracellular Ca(2+) elevation and calcineurin activation. Adenoviral expression of wild‐type DAPK or a constitutively active DAPK mutant significantly enhanced myofibril degeneration and myocyte apoptosis induced in response to β1‐AR stimulation. In contrast, expression of a dominant negative DAPK mutant blocked β1‐AR‐induced myocyte apoptosis and promoted myocyte hypertrophy and myofibril organization. Conclusions: These findings reveal an unprecedented role of DAPK as a regulator of myofibril organization and myocyte apoptosis induced by persistent stimulation of β1‐AR. Thus, modulating DAPK activation to attenuate myofibril degeneration and myocyte death could be considered as a therapy target to treat patients with HF. Grant Funding Source : NIH R01 360998