Abstract 3306: The MIF Receptor (CD74) Regulates AMPK Activation and Cardiac Injury Following Ischemia
Macrophage migration inhibitory factor (MIF) is a cytokine that is highly expressed in the heart and has autocrine/paracrine effects during ischemia-reperfusion. MIF amplifies AMP-activated protein kinase (AMPK) activation during ischemia and inhibits JNK activation during reperfusion. The mechanism mediating these cardioprotective actions of MIF in the heart is uncertain, but may include activation of CD 74, the cell surface MIF receptor. CD74 mediates MIF action in many cell types and is expressed in the heart. Accordingly, to determine the role of CD74 in the heart during ischemia-reperfusion, we subjected isolated perfused hearts from WT and CD74−/− BALB/c mice to 15 min no-flow ischemia and 30 min of reperfusion (n=6 per group). CD74−/− hearts had normal baseline LV contractile function and heart rate (HR), but following ischemia, CD74−/− hearts demonstrated a 60% reduction in AMPK phosphorylation at the Thr172 activation site. During reperfusion, JNK phosphorylation was increased 2-fold in CD74−/− hearts when compared to WT hearts; In addition, with post-ischemic reperfusion, LV contractile function (HR × LV systolic pressure) was decreased in the CD74−/− hearts (40% vs. 80% recovery of baseline function, p<0.05). To address whether CD74 plays a cardioprotective role in the intact heart, anesthetized WT and CD74−/− animals (n=4 per group) were subjected to 20 min left coronary occlusion and 3 hrs of reperfusion. Hearts from CD74−/− mice had 50% less AMPK phosphorylation at the end of ischemia compared to WT (P<0.05). Following 3 hrs of reperfusion, CD74−/− mice showed a 4-fold increase in cardiomyocyte necrosis on TTC (2,3,5-Triphenyltetrazolium chloride) staining when compared to WT (42±3.8 vs. 10±0.7% infarct area/area at risk, P<0.05). In addition, plasma troponin I concentration was higher in the plasma of CD74−/− vs. WT mice after reperfusion (1022±317 vs. 262±25 ng/ml, P<0.05). Thus, the MIF cell surface receptor, CD74, modulates both AMPK activation during ischemia and JNK activation during reperfusion; activation of CD74 by endogenous cardiac ligands including MIF prevents contractile dysfunction and injury during ischemia-reperfusion.
This research has received full or partial funding support from the American Heart Association, Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).