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Impaired macrophage migration inhibitory factor-AMP-activated protein kinase activation and ischemic recovery in the
Heng Ma1, Jingying Wang, D Paul Thomas
1Department of Physiology, Fourth Military Medical University, Xi'an, China.
Insights
Aging impairs the protective AMP-activated protein kinase (AMPK) pathway in the heart, increasing susceptibility to myocardial ischemia. Reduced macrophage migration inhibitory factor (MIF) expression due to aging contributes to this vulnerability.
Area of Science:
- Cardiovascular Research
- Aging Biology
- Molecular Cardiology
Background:
- Elderly individuals exhibit heightened sensitivity to myocardial ischemia, correlating with increased mortality rates.
- Aging significantly impacts cellular signaling pathways, including those crucial for cardiac protection.
Purpose of the Study:
- To investigate the effect of aging on the AMP-activated protein kinase (AMPK) signaling pathway, a key mediator of cardioprotection.
- To elucidate the role of macrophage migration inhibitory factor (MIF) and hypoxia-inducible factor 1alpha (HIF-1α) in age-related alterations of cardiac AMPK activation.
Main Methods:
- Comparative analysis of ischemic AMPK activation in aged versus young murine hearts.
- Assessment of macrophage migration inhibitory factor (MIF) expression and secretion, and hypoxia-inducible factor 1alpha (HIF-1α) levels in aged and young hearts.
- Evaluation of cardiac function and infarct size in MIF knockout mice and aged mice treated with adenovirus encoding MIF.
Main Results:
- Ischemic AMPK activation was significantly impaired in aged murine hearts compared to young hearts.
- Expression and secretion of MIF, an upstream regulator of AMPK, were reduced in aged hearts, linked to decreased HIF-1α levels.
- MIF deficiency exacerbated ischemia-induced contractile dysfunction, while MIF gene delivery in aged mice improved AMPK activation and reduced infarct size.
Conclusions:
- Aging-associated defects in HIF-1α reduce MIF expression, leading to an impaired MIF-AMPK activation response in senescence.
- This impaired pathway contributes to the increased susceptibility of older adults to myocardial ischemia.
- Therapeutic strategies targeting the MIF-AMPK axis may offer protection against myocardial ischemia in the elderly.
Background:
Elderly patients are more sensitive than younger patients to myocardial ischemia, which results in higher mortality. We investigated how aging affects the cardioprotective AMP-activated protein kinase (AMPK) signaling pathway.
Methods And Results:
Ischemic AMPK activation was impaired in aged compared with young murine hearts. The expression and secretion of the AMPK upstream regulator, macrophage migration inhibitory factor (MIF), were lower in aged compared with young adult hearts. Additionally, the levels of hypoxia-inducible factor 1alpha, a known transcriptional activator of MIF, were reduced in aged compared with young hearts. Ischemia-induced AMPK activation in MIF knockout mice was blunted, leading to greater contractile dysfunction in MIF-deficient than in wild-type hearts. Furthermore, intramyocardial injection of adenovirus encoding MIF in aged mice increased MIF expression and ischemic AMPK activation and reduced infarct size.
Conclusions:
An impaired MIF-AMPK activation response in senescence thus may be attributed to an aging-associated defect in hypoxia-inducible factor 1alpha, the transcription factor for MIF. In the clinical setting, impaired cardiac hypoxia-inducible factor 1alpha activation and consequent reduced MIF expression may play an important role in the increased susceptibility to myocardial ischemia observed in older cardiac patients.