Macrophage migration inhibitory factor induces phospholamban phosphorylation in cardiac muscle.

The pleiotropic cytokine macrophage migration inhibitory factor (MIF) elevates sarcoplasmic reticulum (SR) Ca2+ content and enhances Ca2+ transient in cardiac muscle. Our imaging and immunoblot data indicated that the MIF-evoked effect is caused mainly by the phosphorylation of the SR Ca2+-pump regulator phospholamban (PLN). Gene expression data suggested that the cluster of differentiation 74 (CD74) and the C-X-C motif chemokine receptor 7 (CXCR7) form a major MIF receptor complex in cardiomyocytes, but CXCR7 activation alone seemed sufficient to exert the MIF-evoked effect. Our pharmacological assessments suggested that phosphoinositide 3-kinase (PI3K), AKT kinase and endothelial nitric oxide synthase (eNOS) were continuously stimulated in the downstream of CXCR7 activation. Furthermore, NO thus generated likely reacted to activate Ca2+/calmodulin-dependent protein kinase II (CaMKII), leading to PLN phosphorylation and subsequent SR Ca2+-pump activation. Therefore, the CXCR7-PI3K-AKT-eNOS-CaMKII-PLN axis is proposed as a central pathway for MIF-evoked potentiation of cardiac Ca2+ signaling.