β-Adrenergic Receptor Stimulation and Activation of Protein Kinase A Protect Against α1-Adrenergic-Mediated Phosphorylation of Protein Kinase D and Histone Deacetylase 5

Introduction: Chronic activation of beta(1)-adrenergic receptor (beta(1)-AR) signaling can have deleterious effects on the heart, and animal models overexpressing beta(1)-ARs develop a dilated cardiomyopathy and heart failure. In the classic beta-AR pathway, receptor occupancy by an agonist results in increased cyclic adenosine monophosphate (cAMP) levels and activation of protein kinase A (PKA). However, the role of PKA-dependent signaling in the development and progression of cardiomyopathies and heart failure is controversial, because beta-AR signal transduction is generally desensitized in the failing heart and PKA activity is not increased. Methods and Results: Neonatal rat ventricular myocytes were acutely (15 minutes) or chronically (48 hours) treated with isoproterenol, and phosphorylation of protein kinase D (PKD) and histone deacetylase 5 (HDAC5) was measured. Acute beta(1)-AR stimulation or expression of constitutively active (CA) PKA reduced alpha(1)-adrenergic-mediated phosphorylation of HDAC5 and PKD by activation of a phosphatase. Overexpression of CA-PKA also reduced alpha(1)-adrenergic-mediated increased expression of contractile protein fetal isoforms and promoted repression of adult isoforms, but had no effect on alpha(1)-adrenergic-mediated cellular hypertrophy. Conclusions: These data indicate that the PKA-dependent arm of beta-AR signaling can be antihypertrophic and presumably beneficial, through dephosphorylation of PKD and HDAC5 and reduction of hypertrophic fetal isoform gene expression. (I Cardiac Fail 2011;17:592-600)