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

https://doi.org/10.1016/j.bbadis.2019.05.020Get rights and content
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Highlights

  • We examined the effect of CD74 ablation on ethanol-induced cardiac anomalies.

  • CD74 ablation protects against ethanol challenge-induced cardiac contractile anomalies and mitochondrial injury.

  • CD74 inhibition offers benefit against ethanol-induced cardiac anomalies via suppression of AMPK-mediated autophagy.

Abstract

CD74, a non-polymorphic type II transmembrane glycoprotein and MHC class II chaperone, is the cell surface receptor for the inflammatory cytokine macrophage migration inhibitory factor (MIF) and participates in inflammatory signaling regulation. 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, our data revealed that CD74 ablation counteracts acute ethanol challenge-induced myocardial dysfunction, inflammation and apoptosis possibly through an AMPK-mTOR-Skp2-mediated regulation of autophagy.

Abbreviations

AICAR
5′-aminoimidasole-4-carboxamide-1-β-d-ribofuranoside
AMPK
5′ adenosine monophosphate-activated protein kinase
DHE
dihydroethidium
− dL/dt
maximal velocity of relengthening
+ dL/dt
maximal velocity of shortening
EDD
end diastolic dimension
ESD
end systolic dimension
∆FFI
fura-fluorescence intensity change
GFP
green fluorescence Protein
IL
interleukin
LV
left ventricle
MIF
migration inhibitory factor
mTOR
mechanistic target of rapamycin
NCM
Neonatal cardiomyocyte
PS
peak shortening
Sirt
sirtuin
Skp2
S-phase kinase-associated protein 2
TEM
Transmission electron microscopy
TPS
time-to-peak shortening
TR90
time-to-90% relengthening
WT
Wild type

Keywords

CD74
Ethanol
Cardiomyocyte
Autophagy
AMPK
Skp2

Cited by (0)

1

Equal contribution.