β-Adrenergic Receptor Stimulation and Activation of Protein Kinase A Protect Against α1-Adrenergic–Mediated Phosphorylation of Protein Kinase D and Histone Deacetylase 5
| Autor: | Karen Dockstader, Michael R. Bristow, Carmen C. Sucharov, Timothy A. McKinsey, Karin Nunley |
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| Rok vydání: | 2011 |
| Předmět: |
medicine.medical_specialty
Cardiotonic Agents Adrenergic receptor Adrenergic Biology Histone Deacetylases Article Dephosphorylation Receptors Adrenergic alpha-1 Internal medicine medicine Animals Myocytes Cardiac Phosphorylation Protein kinase A Cells Cultured Protein Kinase C Protein kinase C Histone deacetylase 5 Cyclic AMP-Dependent Protein Kinases Rats Enzyme Activation Endocrinology Animals Newborn Adrenergic beta-1 Receptor Agonists Signal transduction Cardiology and Cardiovascular Medicine |
| Zdroj: | Journal of Cardiac Failure. 17:592-600 |
| ISSN: | 1071-9164 |
| Popis: | Introduction Chronic activation of β 1 -adrenergic receptor (β 1 -AR) signaling can have deleterious effects on the heart, and animal models overexpressing β 1 -ARs develop a dilated cardiomyopathy and heart failure. In the classic β-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 β-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 β 1 -AR stimulation or expression of constitutively active (CA) PKA reduced α 1 -adrenergic-mediated phosphorylation of HDAC5 and PKD by activation of a phosphatase. Overexpression of CA-PKA also reduced α 1 -adrenergic–mediated increased expression of contractile protein fetal isoforms and promoted repression of adult isoforms, but had no effect on α 1 -adrenergic–mediated cellular hypertrophy. Conclusions These data indicate that the PKA-dependent arm of β-AR signaling can be antihypertrophic and presumably beneficial, through dephosphorylation of PKD and HDAC5 and reduction of hypertrophic fetal isoform gene expression. |
| Databáze: | OpenAIRE |
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