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Published on: May 19, 2016
Macrophage migration inhibitory factor induces phospholamban phosphorylation in cardiac muscle
Zihan Tang1, Feng Liu1, Miyuki Nishi1
1Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
Abstract:
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.
Insights
Macrophage migration inhibitory factor (MIF) enhances cardiac function by increasing calcium (Ca2+) levels in heart muscle cells. This effect is mediated through the CXCR7 receptor, leading to phospholamban (PLN) phosphorylation and improved calcium handling.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Cell Signaling
Background:
- Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine with known roles in inflammation and immunity.
- Its specific functions in cardiac muscle physiology, particularly concerning calcium handling, are not fully elucidated.
- Understanding MIF's role is crucial for developing targeted therapies for cardiac dysfunction.
Purpose of the Study:
- To investigate the molecular mechanisms by which MIF influences cardiac sarcoplasmic reticulum (SR) Ca2+ content and contractility.
- To identify the specific receptor(s) and signaling pathways involved in MIF-mediated cardiac effects.
- To elucidate the downstream targets of MIF signaling in cardiomyocytes.
Main Methods:
- Cardiac muscle cell imaging and immunoblotting techniques were employed to assess Ca2+ transients and protein phosphorylation.
- Gene expression analysis was performed to identify potential MIF receptors.
- Pharmacological assessments using specific inhibitors were used to delineate signaling pathways.
- Involvement of nitric oxide (NO) and Ca2+/calmodulin-dependent protein kinase II (CaMKII) was investigated.
Main Results:
- MIF significantly elevates SR Ca2+ content and enhances Ca2+ transients in cardiac muscle.
- MIF-induced effects are primarily mediated by the phosphorylation of phospholamban (PLN), a key regulator of the SR Ca2+-pump.
- The cluster of differentiation 74 (CD74) and C-X-C motif chemokine receptor 7 (CXCR7) form a MIF receptor complex, with CXCR7 activation alone being sufficient.
- Downstream signaling involves the activation of phosphoinositide 3-kinase (PI3K), AKT kinase, and endothelial nitric oxide synthase (eNOS), leading to NO production.
- Generated NO activates CaMKII, resulting in PLN phosphorylation and enhanced SR Ca2+-pump activity.
Conclusions:
- The CXCR7-PI3K-AKT-eNOS-CaMKII-PLN signaling axis represents a central pathway for MIF-mediated potentiation of cardiac Ca2+ signaling.
- MIF plays a significant role in regulating cardiac calcium dynamics through this specific molecular pathway.
- This finding opens new avenues for therapeutic interventions targeting MIF signaling in cardiovascular diseases.
