Impaired Macrophage Migration Inhibitory Factor–AMP-Activated Protein Kinase Activation and Ischemic Recovery in the Senescent Heart

Abstract

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 1␣, 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 agingassociated defect in hypoxia-inducible factor 1␣, the transcription factor for MIF. In the clinical setting, impaired cardiac hypoxia-inducible factor 1␣ activation and consequent reduced MIF expression may play an important role in the increased susceptibility to myocardial ischemia observed in older cardiac patients. (Circulation. 2010;122: 282-292.)

Urocortin 2 autocrine/paracrine and pharmacologic effects to activate AMP-activated protein kinase in the heart

“…Mouse hearts were perfused in the Langendorff mode with oxygenated Krebs-Henseleit buffer containing 7 mmol/L glucose, 0.4 mmol/L oleate, 1% BSA, and a low fasting concentration of insulin (10 μU/mL), as previously described (22,55). For ischemia/reperfusion studies, hearts were stabilized at a flow rate of 4 mL/min for 30 min before 15-20 min of no-flow global ischemia, with or without 30 min of reperfusion.…”

“…Myocardial infarction was assessed in hearts excised after 20 min ischemia and 3 h of reperfusion. The heart was stained to delineate the extent of necrosis as a percent of the nonperfused area at risk distal to the coronary occlusion (22,55).…”

Role of macrophage migration inhibitory factor in age-related lung disease

“…Highlighting the role of MIF in inflammation, diverse studies have shown that inhibition of MIF can mitigate deleterious inflammation in conditions such as ARDS, asthma, sepsis, and autoimmunity (8,38,86,120,146). In addition to its immunological function, MIF promotes cellular survival, antioxidant signaling, angiogenesis, and wound repair while mitigating cellular senescence (2,4,21,29,42,47,57,80,82,87,99,100,123,160). This review will highlight the role of MIF in the pathogenesis of respiratory diseases that disproportionately afflict the elderly.…”

Cardioprotection Through S -Nitros(yl)ation of Macrophage Migration Inhibitory Factor

“…MIF regulates key functions in myocardial ischemia/reperfusion (I/R) injury with an overall cardioprotective activity profile. [11][12][13][14] Mechanistically, this property involves protection against c-Jun N-terminal kinase (JNK)-mediated apoptosis and against oxidative cell stress which prominently occurs during the early phase of reperfusion in myocardial infarction. Protection conferred by MIF against redox stress has been attributed to its intrinsic thiol-protein oxidoreductase (TPOR) activity.…”