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Updated: May 4, 2026
Isolation, Characterization, and Purification of Macrophages from Tissues Affected by Obesity-related Inflammation
Published on: April 3, 2017
Macrophage migration inhibitory factor deletion exacerbates pressure overload-induced cardiac hypertrophy through
Xihui Xu1, Yinan Hua, Sreejayan Nair
1Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, 1000 E University Ave, Laramie, WY 82071. jren@uwyo.edu.
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.
Insights
Macrophage migration inhibitory factor (MIF) protects the heart by regulating autophagy. MIF deficiency worsens cardiac hypertrophy, while its presence activates protective pathways, preserving heart function.
Area of Science:
- Cardiology
- Molecular Biology
- Cell Biology
Background:
- Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with known cardioprotective effects.
- The precise molecular mechanisms underlying MIF's cardioprotection, particularly in cardiac hypertrophy, remain incompletely understood.
Purpose of the Study:
- To elucidate the role of MIF in regulating cardiac autophagy and protecting against pressure overload-induced cardiac hypertrophy.
- To investigate the involvement of the AMP-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR) signaling pathway in MIF-mediated cardioprotection.
Main Methods:
- Utilized abdominal aorta constriction (AAC) in wild-type and MIF-deficient mice to model cardiac hypertrophy.
- Employed phenylephrine-induced hypertrophy in H9C2 myoblasts for in vitro mechanistic studies.
- Assessed myocardial autophagy, mitophagy, AMPK-mTOR pathway activation, and Parkin expression.
- Analyzed human failing heart samples for MIF, AMPK, and autophagy levels.
Main Results:
- MIF deficiency exacerbated AAC-induced cardiac hypertrophy and contractile dysfunction, correlating with impaired myocardial autophagy.
- Rapamycin treatment ameliorated hypertrophic responses in MIF-deficient mice, indicating pathway involvement.
- MIF deficiency inhibited phenylephrine-induced mitophagy and AMPK-mTOR-autophagy cascade activation in H9C2 cells.
- Human failing hearts showed elevated levels of MIF, AMPK activation, and autophagy.
Conclusions:
- Endogenous MIF plays a crucial role in preserving cardiac geometry and protecting against hypertrophy by activating the AMPK-mTOR-autophagy pathway.
- MIF regulates mitophagy, a key component of cellular quality control, in response to cardiac stress.
- These findings highlight MIF as a potential therapeutic target for managing cardiac hypertrophy and failure.
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