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Macrophage Migration Inhibitory Factor Antagonizes Pressure Overload-Induced Cardiac Hypertrophy.
MedLine Citation:
PMID:  23144312     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Macrophage migration inhibitory factor (MIF) functions as a pro-inflammatory cytokine when secreted from the cell, but it also exhibits anti-oxidant properties by virtue of its intrinsic oxidoreductase activity. Since increased production of reactive oxygen species (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 wildtype (WT) TAC, and that fibrosis was increased by 4-fold (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 10-fold increase (p< 0.01) in ROS-generating mitochondrial NADPH oxidase (Nox4), and 2- to 3-fold reductions (p< 0.01) in mitochondrial superoxide dismutase (SOD2) and mitochondrial aconitase activities indicated enhanced oxidative injury in the hypertrophied MIF-deficient ventricle. Hypertrophic signaling pathways showed that phosphorylation of cytosolic glycogen synthase kinase-3α (GSK-3α) was greater (p< 0.05) at baseline in the MIF-deficient than WT hearts, and remained elevated after 10d TAC. In the hemodynamically stressed MIF-deficient heart, nuclear p21(CIP1) increased 7-fold (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:
Kiyokazu Koga; Agnes Kenessey; Kaie Ojamaa
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-11-9
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  -     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-12     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
1The Feinstein Institute for Medical Research.
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