Epac1 Functions as a Central Cardioprotective cAMP Effector During Ischemic and β-adrenergic Preconditioning

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.

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.

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.

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.

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.