title: Macrophage migration inhibitory factor deletion exacerbates pressure overload-induced cardiac hypertrophy through mitigating autophagy.
abstract: The proinflammatory cytokine macrophage migration inhibitory factor (MIF) has been shown to be cardioprotective under various pathological conditions. However, the underlying mechanisms still remain elusive. In this study, we revealed that MIF deficiency overtly exacerbated abdominal aorta constriction-induced cardiac hypertrophy and contractile anomalies. MIF deficiency interrupted myocardial autophagy in hypertrophied hearts. Rapamycin administration mitigated the exacerbated hypertrophic responses in MIF(-/-) mice. Using the phenylephrine-induced hypertrophy in vitro model in H9C2 myoblasts, we confirmed that MIF governed the activation of AMP-activated protein kinase-mammalian target of rapamycin-autophagy cascade. Confocal microscopic examination demonstrated that MIF depletion prevented phenylephrine-induced mitophagy in H9C2 myoblasts. Myocardial Parkin, an E3 ubiquitin ligase and a marker for mitophagy, was significantly upregulated after sustained pressure overload, the effect of which was prevented by MIF knockout. Furthermore, our data exhibited that levels of MIF, AMP-activated protein kinase activation, and autophagy were elevated concurrently in human failing hearts. These data indicate that endogenous MIF regulates the mammalian target of rapamycin signaling to activate autophagy to preserve cardiac geometry and protect against hypertrophic responses.
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, 1000 E University Ave, Laramie, WY 82071. jren@uwyo.edu.
authors.forename: Xihui
authors.initials: X
authors.lastname: Xu
authors.forename: Yinan
authors.initials: Y
authors.lastname: Hua
authors.forename: Sreejayan
authors.initials: S
authors.lastname: Nair
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D000818:Animals; D001343:Autophagy; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018613:Microscopy, Confocal; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction
chemical_list: D008263:Macrophage Migration-Inhibitory Factors
keywords: autophagy; cardiac hypertrophy; macrophage migration inhibitory factor; mammalian target of rapamycin; rapamycin