CD74 knockout attenuates alcohol intake-induced cardiac dysfunction through AMPK-Skp2-mediated regulation of autophagy

This study examined the potential role of CD74 in binge drinking-induced cardiac contractile dysfunction. WT and CD74 knockout mice were exposed to ethanol (3 g/kg/d, i.p., for 3 days). Echocardiography, cardiomyocyte function, histological staining and autophagy signaling including AMPK, mTOR, and AMPK downstream signals Skp2 and Sirt1 were evaluated. Our results revealed that ethanol challenge overtly compromised echocardiographic, cardiomyocyte contractile, intracellular Ca2+ and ultrastructural properties along with overt apoptosis, inflammation (elevated MIF, IL-1β and IL-6) and mitochondrial O2– production (p < 0.01), the effect of which was reconciled by CD74 ablation (p < 0.01 vs. ethanol group) with the exception of MIF expression. Ethanol challenge upregulated autophagy (p < 0.001), promoted AMPK phosphorylation and Sirt1 levels (p < 0.003) while suppressing mTOR phosphorylation and Skp2 levels (p < 0.02). These effects were reversed by CD74 ablation. In vitro studies demonstrated that short-term ethanol challenge compromised cardiomyocyte contractile function and facilitated GFP-Puncta formation, which were mitigated by CD74 knockout (p < 0.0001). Moreover, the CD74 ablation-offered beneficial effects against ethanol-induced cardiomyocyte dysfunction, and GFP-Puncta formation were nullified by the AMPK activator AICAR, the Skp2 inhibitor C1 or the Sirt1 activator SRT1720 (p < 0.0001). Taken together, ou...

Source: Biochimica et Biophysica Acta (BBA) Molecular Basis of Disease - June 2, 2019 Category: Molecular Biology Source Type: research