Abstract P215: Role for Reduced MIF Secretion in Attenuated AMPK Activation and Ischemic Recovery in the Senescent Heart
An important role for a macrophage migration inhibitory factor (MIF)-AMP-activated protein kinase (AMPK) signaling pathway in ameliorating myocardial damage following ischemia/reperfusion (I/R) in the senescent heart has been described. An aging-associated reduction in AMPK activity may be due to a decline in the ability of cardiac cells to activate the MIF-AMPK cascade, thereby resulting in reduced tolerance to ischemic insults. To test this hypothesis, in vivo regional ischemia was induced by occlusion of the left anterior descending (LAD) coronary artery in young adult (4–6 months) and aged (24–26 months) mice. The ischemic AMPK activation response was impaired in aged compared to young hearts. Compared to young adult hearts, larger infarct size and poorer left ventricular function were documented in aged hearts post- I/R; these effects were reversed by the AMPK activator, resveratol (10 μM). Notably, cardiac MIF expression and secretion in aged hearts was lower than in young hearts. Ischemia induced AMPK activation in MIF knock-out (MIF KO) and CD74-deficient (the MIF receptor, CD74 KO) hearts were blunted, leading to greater contractile dysfunction in ischemic hearts when compared to wild type (WT) mice. Hypoxia exposure resulted in depressed peak shortening (PS) and maximal velocity of shortening/relengthening (±dL/dt), and prolonged time-to-90% relengthening (TR90) of both young and aged cardiomyocytes. Nonetheless, the extent of hypoxic dysfunction was accentuated in aged (p<0.05 vs. young). Exogenous recombinant MIF (10 ng/ml) restored hypoxia-stimulated AMPK activation in aged cardiomyocytes and partially restored contractile function in hypoxia (p<0.05). Finally, intramyocardial injection of adenovirus encoding MIF (Adv-MIF, 5×109 IFU/ml) in aged mice increased cardiac MIF expression and ischemic AMPK activity and markedly reduced infarct size compared to aged or control adenoviral (adv-LacZ) injected hearts (p<0.05). We conclude that an aging-associated reduction in ischemia-induced AMPK activation contributes to ischemic intolerance in senescent hearts. Depressed cardiac MIF expression and secretion may play an important role in the observed increase in susceptibility to myocardial ischemia associated with aging.
This research has received full or partial funding support from the American Heart Association, National Center.