title: Macrophage migration inhibitory factor promotes expression of GLUT4 glucose transporter through MEF2 and Zac1 in cardiomyocytes.
abstract: OBJECTIVE
  Evidence shows that both macrophage migration inhibitory factor (MIF) and GLUT4 glucose transporter are involved in diabetic cardiomyopathy (DCM), but it remains largely unknown whether and how MIF regulates GLUT4 expression in cardiomyocytes. The present study aims to investigate the mechanism underlying the modulation of GLUT4 by MIF in cardiomyocytes.
  
  
  METHODS
  Activations of AKT and AMPK signaling, and expressions of MIF, GLUT4 and the candidate GLUT4 regulation associated transcription factors in the diabetic mouse myocardium were determined. The screened transcription factors mediating MIF-promoted GLUT4 expression were verified by RNA interference (RNAi) and electrophoretic mobility shift assay (EMSA), respectively.
  
  
  RESULTS
  MIF was increased, but GLUT4 was decreased in the diabetic mouse myocardium. MIF could enhance glucose uptake and up-regulate GLUT4 expression in NMVCs. Expressions of transcription factor MEF2A, -2C, -2D and Zac1 were significantly up-regulated in MIF-treated neonatal mouse ventricular cardiomyocytes (NMVCs), and markedly reduced in the diabetic myocardium. Knockdown of MEF2A, -2C, -2D and Zac1 could significantly inhibit glucose uptake and GLUT4 expression in cardiomyocytes. Moreover, EMSA results revealed that transcriptional activities of MEF2 and Zac1 were significantly increased in MIF-treated NMVCs. AMPK signaling was activated in MIF-stimulated NMVCs, and AMPK activator AICAR could enhance MEF2A, -2C, -2D, Zac1 and GLUT4 expression. Additionally, MIF effects were inhibited by an AMPK inhibitor compound C and siRNA targeting MIF receptor CD74, suggesting the involvement of CD74-dependent AMPK activation.
  
  
  CONCLUSIONS
  Transcription factor MEF2 and Zac1 mediate MIF-induced GLUT4 expression through CD74-dependent AMPK activation in cardiomyocytes.
authors.affiliation: Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou, China. Electronic address: 13416492503@163.com.
authors.forename: Yeyou
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Medical Research Center of Guangdong General Hospital, Guangdong Provincial Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangzhou, China. Electronic address: weiweiyuan@163.com.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Yuan
authors.affiliation: Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou, China. Electronic address: zjgylyy2323@163.com.
authors.forename: Wensi
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Medical Research Center of Guangdong General Hospital, Guangdong Provincial Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangzhou, China. Electronic address: zhujiening0323@163.com.
authors.forename: Jiening
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Medical Research Center of Guangdong General Hospital, Guangdong Provincial Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangzhou, China. Electronic address: linqx@aliyu.com.
authors.forename: Qiuxiong
authors.initials: Q
authors.lastname: Lin
authors.affiliation: Medical Research Center of Guangdong General Hospital, Guangdong Provincial Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangzhou, China. Electronic address: 913175382@qq.com.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zou
authors.affiliation: Medical Research Center of Guangdong General Hospital, Guangdong Provincial Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangzhou, China. Electronic address: chunyudeng@hotmail.com.
authors.forename: Chunyu
authors.initials: C
authors.lastname: Deng
authors.affiliation: Medical Research Center of Guangdong General Hospital, Guangdong Provincial Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangzhou, China. Electronic address: macklefu@163.com.
authors.forename: Yongheng
authors.initials: Y
authors.lastname: Fu
authors.affiliation: The Libin Cardiovascular Institute of AB, Department of Biochemistry & Molecular Biology, Cumming School of Medicine, The University of Calgary, Calgary, Canada. Electronic address: xlzheng@ucalgary.ca.
authors.forename: Xilong
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Medical Research Center of Guangdong General Hospital, Guangdong Provincial Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangzhou, China. Electronic address: mnmyang@aliyun.com.
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.affiliation: Medical Research Center of Guangdong General Hospital, Guangdong Provincial Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangzhou, China. Electronic address: doctorwushulin@163.com.
authors.forename: Shulin
authors.initials: S
authors.lastname: Wu
authors.affiliation: Medical Research Center of Guangdong General Hospital, Guangdong Provincial Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangzhou, China. Electronic address: yuxycn@hotmail.com.
authors.forename: Xiyong
authors.initials: X
authors.lastname: Yu
authors.affiliation: Medical Research Center of Guangdong General Hospital, Guangdong Provincial Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangzhou, China. Electronic address: zhixinshan@aliyun.com.
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Shan
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000502:physiology; D018797:Cell Cycle Proteins / Q000502:physiology*; D002478:Cells, Cultured; D058065:Diabetic Cardiomyopathies / Q000503:physiopathology; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D051275:Glucose Transporter Type 4 / Q000235:genetics*; D000949:Histocompatibility Antigens Class II / Q000502:physiology; D019746:Intramolecular Oxidoreductases / Q000502:physiology*; D064326:MEF2 Transcription Factors / Q000502:physiology*; D008263:Macrophage Migration-Inhibitory Factors / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011972:Receptor, Insulin / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology*; D016277:Ventricular Function, Left
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D018797:Cell Cycle Proteins; D051275:Glucose Transporter Type 4; D000949:Histocompatibility Antigens Class II; D064326:MEF2 Transcription Factors; D008263:Macrophage Migration-Inhibitory Factors; C498423:Plagl1 protein, mouse; C495693:Slc2a4 protein, mouse; D014157:Transcription Factors; C045084:invariant chain; D011972:Receptor, Insulin; D055372:AMP-Activated Protein Kinases; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse
keywords: Cardiomyocyte; GLUT4; MEF2; Macrophage migration inhibitory factor; Zac1