Impaired macrophage migration inhibitory factor-AMP-activated protein kinase activation and ischemic recovery in the senescent heart
Open accessAbstract
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.
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AMPK decreased apoptosis, improved post-ischemic recovery, and limited myocardial infarction.
“Mechanically, AMPK increased glucose uptake and glucose transporter 4 translocation [171], decreased apoptosis, improved post-ischemic recovery, and limited myocardial infarction (MI) [172,173].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [172]
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References 40 · Cited by 164
- Authors
- Ma, H., Wang, J., Thomas, D. P., Tong, C., Leng, L., Wang, W., Merk, M., Zierow, S., Bernhagen, J., Ren, J., Bucala, R., & Li, J.
- Affiliations
- University of Wyoming (US)
- From the Department of Physiology, Fourth Military Medical University, Xi'an, China (H.M.); Divisions of Pharmaceutical Sciences (H.M., J.R., J.L.) and Kinesiology and Health (D.P.T.), University of Wyoming, Laramie; Department of Pharmacology and Toxicology, University at Buffalo–SUNY, Buffalo, NY (J.W., C.T., J.L.); Department of Medicine, Yale School of Medicine, New Haven, Conn (L.L., W.W., M.M., S.Z., R.B.); and University Hospital RWTH Aachen, Aachen, Germany (J.B.).
- Venue
- Circulation
- Published
- 2010-07-20
- Volume
- 122
- Issue
- 3
- Pages
- 282-292
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC2907453
- OpenAlex
- W2158498082
- Cited by
- 164
- References
- 40
- Citations by year
- 2025: 7 · 2024: 11 · 2023: 8 · 2022: 7 · 2021: 7 · 2020: 9 · 2019: 14 · 2018: 13 · 2017: 10 · 2016: 13 · 2015: 14 · 2014: 17 · 2013: 15 · 2012: 10
- FWCI
- 7.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Funders
- National Institute on Aging (R03AG028163)
- National Institute of Allergy and Infectious Diseases (R01AI04230, R01AI042310)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Life Sciences › Immunology and Microbiology › Immunology › Macrophage Migration Inhibitory Factor
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Keywords
- macrophage migration inhibitory factor, AMPK, cardiac aging, myocardial ischemia, hypoxia-inducible factor-1α, infarct size, cardiac contractile dysfunction, cardioprotection, MIF knockout mice, adenoviral gene transfer
- MeSH terms
- Resveratrol, Aging, Animals, Enzyme Inhibitors, Macrophage Migration-Inhibitory Factors, Myocardial Infarction, Myocardium, Phenotype, Phosphorylation, Stilbenes, Ultrasonography, Signal Transduction, Down-Regulation, Ventricular Function, Left, Myocardial Ischemia, Mice, Knockout, Intramolecular Oxidoreductases, Myocytes, Cardiac, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, AMP-Activated Protein Kinases
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