title: Hyperglycemic myocardial damage is mediated by proinflammatory cytokine: macrophage migration inhibitory factor.
abstract: BACKGROUND
  Diabetes has been regarded as an inflammatory condition which is associated with left ventricular diastolic dysfunction (LVDD). The purpose of this study was to examine the expression levels of macrophage migration inhibitory factor (MIF) and G protein-coupled receptor kinase 2 (GRK2) in patients with early diabetic cardiomyopathy, and to investigate the mechanisms involved in MIF expression and GRK2 activation.
  
  
  METHODS
  83 patients in the age range of 30-64 years with type 2 diabetes and 30 matched healthy men were recruited. Left ventricular diastolic function was evaluated by cardiac Doppler echocardiography. Plasma MIF levels were determined by ELISA. To confirm the clinical observation, we also studied MIF expression in prediabetic rats with impaired glucose tolerance (IGT) and relationship between MIF and GRK2 expression in H9C2 cardiomyoblasts exposed to high glucose.
  
  
  RESULTS
  Compared with healthy subjects, patients with diabetes have significantly increased levels of plasma MIF which was further increased in diabetic patients with Left ventricular diastolic dysfunction (LVDD). The increased plasma MIF levels in diabetic patients correlated with plasma glucose, glycosylated hemoglobin and urine albumin levels. We observed a significant number of TUNEL-positive cells in the myocardium of IGT-rats but not in the control rats. Moreover, we found higher MIF expression in the heart of IGT with cardiac dysfunction compared to that of the controls. In H9C2 cardiomyoblast cells, MIF and GRK2 expression was significantly increased in a glucose concentration-dependant manner. Furthermore, GRK2 expression was abolished by siRNA knockdown of MIF and by the inhibition of CXCR4 in H9C2 cells.
  
  
  CONCLUSIONS
  Our findings indicate that hyperglycemia is a causal factor for increased levels of pro-inflammatory cytokine MIF which plays a role in the development of cardiomyopathy occurring in patients with type 2 diabetes. The elevated levels of MIF are associated with cardiac dysfunction in diabetic patients, and the MIF effects are mediated by GRK2.
authors.affiliation: Medical Research Center, Guangdong Provincial Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China. yuxycn@hotmail.com
authors.forename: Xi-Yong
authors.initials: XY
authors.lastname: Yu
authors.forename: Hong-Mei
authors.initials: HM
authors.lastname: Chen
authors.forename: Jia-Liang
authors.initials: JL
authors.lastname: Liang
authors.forename: Qiu-Xiong
authors.initials: QX
authors.lastname: Lin
authors.forename: Hong-Hong
authors.initials: HH
authors.lastname: Tan
authors.forename: Yong-Heng
authors.initials: YH
authors.lastname: Fu
authors.forename: Xiao-Ying
authors.initials: XY
authors.lastname: Liu
authors.forename: Zhi-Xin
authors.initials: ZX
authors.lastname: Shan
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Li
authors.forename: Hua-Zhang
authors.initials: HZ
authors.lastname: Yang
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.forename: Yangxin
authors.initials: Y
authors.lastname: Li
authors.forename: Shu-Guang
authors.initials: SG
authors.lastname: Lin
mesh_terms: D000328:Adult; D000818:Animals; D016022:Case-Control Studies; D016207:Cytokines / Q000276:immunology*; D003924:Diabetes Mellitus, Type 2; D058065:Diabetic Cardiomyopathies / Q000209:etiology* / Q000276:immunology; D054769:G-Protein-Coupled Receptor Kinase 2; D006331:Heart Diseases / Q000209:etiology* / Q000276:immunology; D006801:Humans; D006943:Hyperglycemia / Q000150:complications* / Q000276:immunology; D008263:Macrophage Migration-Inhibitory Factors / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D051381:Rats
chemical_list: D016207:Cytokines; D008263:Macrophage Migration-Inhibitory Factors; C496567:GRK2 protein, human; D054769:G-Protein-Coupled Receptor Kinase 2