Cardiotoxic and cardioprotective features of chronic β-adrenergic signaling.

RATIONALE:In the failing heart, persistent β-adrenergic receptor activation is thought to induce myocyte death by protein kinase A and activation of calcium/calmodulin-dependent kinase II. β-adrenergic signaling pathways also are capable of activating cardioprotective mechanisms. OBJECTIVE:This study used a novel inhibitor peptide to inhibit duanyu1529 activity to test the hypothesis that β-adrenergic receptor signaling causes cell death through pathways and cardioprotection through duanyu1529-independent pathways. METHODS AND RESULTS:In duanyu1529 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, duanyu1529 inhibition protected myocytes from death induced by β1-adrenergic receptor agonists by preventing cytosolic and sarcoplasmic reticulum Ca(2+) overload and calcium/calmodulin-dependent kinase II activation. duanyu1529 inhibition revealed a cardioprotective role of β-adrenergic signaling via cAMP/exchange protein directly activated by cAMP/Rap1/Rac/extracellular signal-regulated kinase pathway. Selective duanyu1529 inhibition causes protection in the heart after myocardial infarction that was superior to β-blocker therapy. CONCLUSIONS:These results suggest that selective block of duanyu1529 could be a novel heart failure therapy.

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