title: Macrophage migration inhibitory factor antagonizes pressure overload-induced cardiac hypertrophy.
abstract: Macrophage migration inhibitory factor (MIF) functions as a proinflammatory cytokine when secreted from the cell, but it also exhibits antioxidant properties by virtue of its intrinsic oxidoreductase activity. Since increased production of ROS is implicated in the development of left ventricular hypertrophy, we hypothesized that the redox activity of MIF protects the myocardium when exposed to hemodynamic stress. In a mouse model of myocardial hypertrophy induced by transverse aortic coarctation (TAC) for 10 days, we showed that growth of the MIF-deficient heart was significantly greater by 32% compared with wild-type (WT) TAC hearts and that fibrosis was increased by fourfold (2.62 ± 0.2% vs. 0.6 ± 0.1%). Circulating MIF was increased in TAC animals, and expression of MIF receptor, CD74, was increased in the hypertrophic myocardium. Gene expression analysis showed a 10-fold increase (P < 0.01) in ROS-generating mitochondrial NADPH oxidase and 2- to 3-fold reductions (P < 0.01) in mitochondrial SOD2 and mitochondrial aconitase activities, indicating enhanced oxidative injury in the hypertrophied MIF-deficient ventricle. Hypertrophic signaling pathways showed that phosphorylation of cytosolic glycogen synthase kinase-3α was greater (P < 0.05) at baseline in MIF-deficient hearts than in WT hearts and remained elevated after 10-day TAC. In the hemodynamically stressed MIF-deficient heart, nuclear p21(CIP1) increased sevenfold (P < 0.01), and the cytosolic increase of phospho-p21(CIP1) was significantly greater than in WT TAC hearts. We conclude that MIF antagonizes myocardial hypertrophy and fibrosis in response to hemodynamic stress by maintaining a redox homeostatic phenotype and attenuating stress-induced activation of hypertrophic signaling pathways.
authors.affiliation: Center for Heart and Lung Research, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
authors.forename: Kiyokazu
authors.initials: K
authors.lastname: Koga
authors.forename: Agnes
authors.initials: A
authors.lastname: Kenessey
authors.forename: Kaie
authors.initials: K
authors.lastname: Ojamaa
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism; D001011:Aorta / Q000503:physiopathology / Q000601:surgery; D062186:Arterial Pressure; D006332:Cardiomegaly / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis; D005786:Gene Expression Regulation; D005838:Genotype; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008026:Ligation; D008263:Macrophage Migration-Inhibitory Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010641:Phenotype; D010766:Phosphorylation; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D014161:Transduction, Genetic; D014162:Transfection; D020257:Ventricular Remodeling; D000099156:Superoxide Dismutase 2
chemical_list: D000154:Aconitate Hydratase; D000944:Antigens, Differentiation, B-Lymphocyte; D050759:Cyclin-Dependent Kinase Inhibitor p21; D038362:Glycogen Synthase Kinase 3; D000949:Histocompatibility Antigens Class II; D019746:Intramolecular Oxidoreductases; D008263:Macrophage Migration-Inhibitory Factors; D019255:NADPH Oxidases; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C493957:Cdkn1a protein, mouse; C045084:invariant chain; C448021:glycogen synthase kinase 3 alpha; C076231:Mif protein, mouse