title: Macrophage Migration Inhibitory Factor (MIF) Deficiency Exacerbates Aging-Induced Cardiac Remodeling and Dysfunction Despite Improved Inflammation: Role of Autophagy Regulation.
abstract: Aging leads to unfavorable geometric and functional sequelae in the heart. The proinflammatory cytokine macrophage migration inhibitory factor (MIF) plays a role in the maintenance of cardiac homeostasis under stress conditions although its impact in cardiac aging remains elusive. This study was designed to evaluate the role of MIF in aging-induced cardiac anomalies and the underlying mechanism involved. Cardiac geometry, contractile and intracellular Ca(2+) properties were examined in young (3-4 mo) or old (24 mo) wild type and MIF knockout (MIF(-/-)) mice. Our data revealed that MIF knockout exacerbated aging-induced unfavorable structural and functional changes in the heart. The detrimental effect of MIF knockout was associated with accentuated loss in cardiac autophagy with aging. Aging promoted cardiac inflammation, the effect was attenuated by MIF knockout. Intriguingly, aging-induced unfavorable responses were reversed by treatment with the autophagy inducer rapamycin, with improved myocardial ATP availability in aged WT and MIF(-/-) mice. Using an in vitro model of senescence, MIF knockdown exacerbated doxorubicin-induced premature senescence in H9C2 myoblasts, the effect was ablated by MIF replenishment. Our data indicated that MIF knockout exacerbates aging-induced cardiac remodeling and functional anomalies despite improved inflammation, probably through attenuating loss of autophagy and ATP availability in the heart.
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071 USA.
authors.forename: Xihui
authors.initials: X
authors.lastname: Xu
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071 USA.|Department of Emergency, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, PR China.
authors.forename: Jiaojiao
authors.initials: J
authors.lastname: Pang
authors.affiliation: Department of Emergency, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, PR China.
authors.forename: Yuguo
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Medicine, Yale School of Medicine, New Haven, CT 06520 USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071 USA.|Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China.
authors.forename: Yingmei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071 USA.|Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000375:Aging / Q000235:genetics / Q000276:immunology*; D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics; D006321:Heart / Q000187:drug effects*; D007249:Inflammation / Q000235:genetics / Q000276:immunology*; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology; D020123:Sirolimus / Q000008:administration & dosage; D020257:Ventricular Remodeling / Q000235:genetics / Q000276:immunology*
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D000255:Adenosine Triphosphate; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse; D020123:Sirolimus