Impaired macrophage migration inhibitory factor-AMP-activated protein kinase activation and ischemic recovery in the senescent heart.
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.


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.
Ma
Heng
H
Department of Physiology, Fourth Military Medical University, Xi'an, China.
Wang
Jingying
J
Thomas
D Paul
DP
Tong
Chao
C
Leng
Lin
L
Wang
Wenkui
W
Merk
Melanie
M
Zierow
Swen
S
Bernhagen
Jürgen
J
Ren
Jun
J
Bucala
Richard
R
Li
Ji
J
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000375:Aging / Q000502:physiology*; D000818:Animals; D015536:Down-Regulation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000235:genetics* / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism; D017202:Myocardial Ischemia / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013267:Stilbenes / Q000494:pharmacology; D014463:Ultrasonography; D016277:Ventricular Function, Left / Q000502:physiology
D004791:Enzyme Inhibitors; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008263:Macrophage Migration-Inhibitory Factors; D013267:Stilbenes; D055372:AMP-Activated Protein Kinases; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse; D000077185:Resveratrol