Epac1 participates in β1-adrenoreceptor autoantibody-mediated decreased autophagic flux in cardiomyocytes.

Abstract

Decreased autophagic flux in cardiomyocytes is an important mechanism by which the β1-adrenoreceptor (β1-AR) autoantibody (β1-AA) induces heart failure. A previous study found that β1-AA imparts its biological effects via the β1-AR/Gs/AC/cAMP/PKA canonical signaling pathway, but PKA inhibition does not completely reverse β1-AA-induced reduction in autophagy in myocardial tissues, suggesting that other signaling molecules participate in this process. This study confirmed that Epac1 upregulation is indeed involved β1-AA-induced decreased cardiomyocyte autophagy through CE3F4 pretreatment, Epac1 siRNA transfection, western blot and immunofluorescence methods. On this basis, we constructed β1-AR and β2-AR knockout mice, and used receptor knockout mice, β1-AR selective blocker (atenolol), and the β2-AR/Gi-biased agonist ICI 118551 to show that β1-AA upregulated Epac1 expression through β1-AR and β2-AR to inhibit autophagy, and biased activation of β2-AR/Gi signaling downregulated myocardial Epac1 expression to reverse β1-AA-induced myocardial autophagy inhibition. This study aimed to test the hypothesis that Epac1 acts as another effector downstream of cAMP on β1-AA-induced reduction in cardiomyocyte autophagy, and β1-AA upregulates myocardial Epac1 expression through β1-AR and β2-AR, and biased activation of the β2-AR/Gi signaling pathway can reverse β1-AA-induced myocardial autophagy inhibition. This study provides new ideas and therapeutic targets for the prevention and treatment of cardiovascular diseases related to dysregulated autophagy.