Abstract 16144: Death Associated Protein Kinase Mediates Myofibril Degeneration and Myocyte Apoptosis Induced by Beta-adrenergic Receptors
Background: Death associated protein kinase (DAPK) is a novel Ca2+/calmodulin-regulated serine/threonine kinase that regulates cytoskeletal dynamics and cell death. Because chronic activation of Ca2+/calmodulin-dependent pathway has been implicated in the deleterious effects of β-adrenergic receptor (β-AR) signaling in the heart, we investigated the functions of DAPK activation in cardiomyocytes and in heart in response to acute and chronic stimulation of β-ARs.
Methods and Results: DAPK expression and activation was increased in human dilated cardiomyopathy heart samples compared to non-failing controls and in heart of mice treated with isoproterenol (30 mg/kg/d), thus pointing to a possible role of DAPK in the development of heart failure. Treatment of mice with DAPK inhibitor (5 mg/kg/d, i.p) significantly reduced myocyte apoptosis, attenuated cardiac fibrosis and improved cardiac contractile function induced after isoproterenol infusion for 7 days. Consistent with this effect of β-AR stimulation in vivo, chronic treatment of cultured neonatal rat cardiomyocytes with β1-AR agonists or adenoviral expression of β1-ARs caused DAPK activation and interaction with focal adhesion kinase (FAK). This β1-AR-induced DAPK expression/activation was dependent on intracellular Ca2+/calmodulin signaling pathway activation and on protein phosphatase PTEN activation. Adenoviral expression of a kinase-defective mutant of DAPK (K42A) blocked β1-AR-induced stress kinases, focal adhesion signaling downregulation and myocyte apoptosis. In contrast, transduction of myocytes with adenovirus harboring wild-type DAPK or a constitutively active DAPK mutant (ΔCaM) significantly enhanced focal adhesion signaling and myofibril degeneration and myocyte apoptosis in response to β1-AR stimulation.
Conclusions: These data point to unidentified role of DAPK as a Ca2+/calmodulin kinase involved in the regulation of myofibril organization and myocyte apoptosis induced by chronic stimulation of β1-AR and suggest that DAPK activation could contribute to the pathogenesis effects of β-AR signaling during the progression to heart failure.
Author Disclosures: X. Guo: None. B. Hooshdaran: None. K. Rafiq: None. H. Xi: None. M. Kolpakov: None. S. Liu: None. X. Zhang: None. X. Chen: None. S.R. Houser: None. W.J. Koch: None. A. Sabri: None.
- © 2016 by American Heart Association, Inc.