Epac2 O-GlcNAcylation, a new player in high glucose-mediated cardiac calcium mishandling

Introduction Epidemiological and preclinical studies have pointed out a correlation between hyperglycemia and increasing risk of heart failure. In cardiomyocytes, hyperglycemia has been shown to alter Ca2+ signaling via CaMKII a downstream effector of Epac2, a key player in Ca2+ mishandling. However the role of Epac2 in high-glucose (HG) mediated Ca2+ dysregulation is unclear. Objective To test the involvement of Epac2 in hyperglycemia-mediated cardiac Ca2+ mishandling. Method Ca2+ signaling was measured by confocal microscopy in Fluo-4 loaded ventricular cardiomyocytes isolated from C57BL6 and Epac2-KO mice and treated with different glucose concentrations. Results HG (500 mg/dL) enhanced the occurrence of Ca2+ sparks and pro-arrhythmic events in WT mice but not in Epac2 KO. This increase was prevented by Epac2 pharmacological inhibition (ESI-05 10 μM) (Ca2+ sparks frequency [#/s/100 μm]: 1.07 ± 0.39 for HG vs. 0.16 ± 0.06 for normal glucose [NG, 100 mg/dL], P  Conclusion Our work shows an Epac2 O-GlcNAcylation by HG responsible for pro-arrhythmic SR Ca2+ leak in cardiomyocytes, a new mechanism that might be involved in diabetic cardiomyopathy.