Macrophage migration inhibitory factor promotes the expression of GLUT4 glucose transporter through MEF2 and Zacl in cardiomyocytes

Background Evidences show that macrophage migration inhibitory factor （MIF） and the subtype 4 form of glucose transporter （GLUT4） participate in the process of diabetic cardiomyopathy （DCM）, however the effect of MIF on modulation of GLUT4 expression is not clear. The present study aimed to investigate the mechanism underlying the modulation of GLUT4 by MIF in cardiomyocytes. Methods The neonatal C57BL/ 6 mouse ventricular cardiomyocytes （NMVCs） were isolated for in vitro studies. Expressions of GLUT4 and the candidate GLUT4 regulation associated transcription factors in mouse myocardium and NMVCs were determined by quantitative reverse transcription PCR （qRT-PCR）, and Western blotting, respectively. The effects of screened transcription factors on mediating MIF-promoted GLUT4 expression were verified by RNA interference （RNAi） assay. Results MIF was upregulated, but GLUT4 was decreased in the diabetic myocardium of the db/db mice. MIF could enhance glucose uptake of the cultured neonatal mouse cardiomyocytes with significant upregulation of GLUT4. RT-qPCR and Western-blot assays showed that MEF2A, -2C, -2D and Zacl were significantly up-regulated in MIF-treated NMVCs. Knockdown of Zacl, MEF2A, -2C, and -2D could markedly inhibit glucose uptake and GLUT4 expression in cardiomyocytes. Moreover, Zacl was also shown directly regulated by MEF2A, -2C, and -2D, respectively. Conclusions Transcription factors Zacl and MEF2 mediate MIF-promoted GLUT4 expression in cardiomyocytes.