Cardiotoxic and Cardioprotective Features of Chronic β-Adrenergic Signaling

Rationale: In the failing heart, persistent beta-adrenergic receptor activation is thought to induce myocyte death by protein kinase A (PKA)-dependent and PKA-independent activation of calcium/calmodulin-dependent kinase II. beta-adrenergic signaling pathways also are capable of activating cardioprotective mechanisms. Objective: This study used a novel PKA inhibitor peptide to inhibit PKA activity to test the hypothesis that beta-adrenergic receptor signaling causes cell death through PKA-dependent pathways and cardioprotection through PKA-independent pathways. Methods and Results: In PKA inhibitor peptide transgenic mice, chronic isoproterenol failed to induce cardiac hypertrophy, fibrosis, and myocyte apoptosis, and decreased cardiac function. In cultured adult feline ventricular myocytes, PKA inhibition protected myocytes from death induced by beta 1-adrenergic receptor agonists by preventing cytosolic and sarcoplasmic reticulum Ca2+ overload and calcium/calmodulin-dependent kinase II activation. PKA inhibition revealed a cardioprotective role of beta-adrenergic signaling via cAMP/exchange protein directly activated by cAMP/Rap1/Rac/extracellular signal-regulated kinase pathway. Selective PKA inhibition causes protection in the heart after myocardial infarction that was superior to beta-blocker therapy. Conclusions: These results suggest that selective block of PKA could be a novel heart failure therapy. (Circ Res. 2013;112:498-509.)