Abstract / Summary
Abstract Background β-adrenergic receptor (β-AR) stimulated cAMP signaling may be impaired in pathophysiological conditions such as myocardial ischemia and heart failure, highlighting the need for cardioprotective strategies bypassing β-ARs, directly targeting downstream cAMP effectors. cAMP signaling has traditionally been attributed to protein kinase A (PKA), while contribution of the alternative cAMP effector Epac1 remains controversial. Objective To examine whether Epac1 is required for cardioprotection induced by ischemic preconditioning (IPC) and β-adrenergic preconditioning (β-PC), and to identify downstream signaling pathways. Methods Langendorff-perfused hearts from wild-type (WT) and Epac1-deficient (Epac1 −/− ) mice were subjected to global ischemia and reperfusion. Complementary experiments were performed in human cardiac-derived cells exposed to simulated ischemia–reoxygenation (sIR) with pharmacological modulation of Epac1, PKA, Akt, and STAT3. Results IPC and β-PC significantly reduced infarct size in WT hearts but failed to confer protection in Epac1 −/− hearts, demonstrating that Epac1 is essential for IPC- and β-PC mediated cardioprotection. Consistently, pharmacological inhibition of Epac1 abolished IPC- and β-PC induced protection in vitro . Direct activation of Epac1 with the selective agonist I942 markedly reduced cell death and increased phosphorylation of Akt, GSK3β, and STAT3. Inhibition of Akt or STAT3 completely eliminated Epac1-mediated protection, indicating that both RISK- and SAFE-associated signaling are required. In contrast, selective PKA activation failed to induce protection in either WT or Epac1 −/− hearts, although PKA inhibition partially attenuated IPC- and β-PC-induced protection, consistent with a permissive rather than primary effector role for PKA. Conclusion Epac1 mediates IPC and β-PC induced cardioprotection through Akt/GSK3β- and STAT3-dependent signaling, supporting Epac1 as a promising β-AR-independent therapeutic target.