Abstract 309: Small-molecule PDE4 Activators Limit Isoproterenol-induced Hypertrophy in Rat Neonatal Cardiomyocytes

Abstract

Increasing the cellular levels of the second messenger cAMP, such as via activation of β-adrenergic receptors (βARs), is the most powerful mechanism to acutely increase cardiac output. However, chronic βAR stimulation predisposes to the development of heart failure (HF) by promoting arrhythmias and pathologic cardiac hypertrophy. Cardiac myocyte cAMP levels are tightly regulated by cyclic nucleotide phosphodiesterases (PDEs), a family of isoenzymes that hydrolyze and inactivate cAMP. Prior studies have shown that development of HF is associated with a downregulation of the expression and activity of Type 4 PDEs (PDE4s) in humans and animals. We propose that this reduction in PDE4 is maladaptive and may contribute to the development of HF, because genetic or pharmacologic inactivation of PDE4s is associated with an increased propensity to arrhythmias and development of pathologic cardiac hypertrophy. We propose that, conversely, an increase in PDE4 protein and/or activity would be cardioprotective. To test this hypothesis, we have utilized rat neonatal cardiomyocytes (RNCM) in culture as a model system. Long term treatment with Isoproterenol (Iso) induces hypertrophy in these cells as reflected by increased cell surface/size. To stimulate PDE4 activity, which contributes about 50% of the total cAMP-PDE activity in RNCMs, cells were treated with small-molecule PDE4 activators, which we recently identified in a high throughout screen. We find that small-molecule PDE4 activators reduce Iso-induced cellular cAMP levels as measured by enzyme immuno assay and suppress Iso-induced PKA signaling, such as the PKA-mediated phosphorylation of phospholamban. Moreover, treatment with PDE4 activators alleviates the Iso-dependent increase in cell size in RNCM indicating that pharmacologic PDE4 activation can serve to limit cardiomyocyte hypertrophy.