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J. Am. Coll. Cardiol. · Apr 2008
Aging mouse hearts are refractory to infarct size reduction with post-conditioning.
- Karin Przyklenk, Michelle Maynard, Chad E Darling, and Peter Whittaker.
- Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA. kprzykle@med.wayne.edu
- J. Am. Coll. Cardiol. 2008 Apr 8; 51 (14): 1393-8.
ObjectivesOur aim was to establish whether the efficacy of post-conditioning is maintained in aging hearts.BackgroundPost-conditioning, or relief of myocardial ischemia in a stuttered manner, has been shown to reduce infarct size, in part because of up-regulation of survival kinases (extracellular-signal regulated kinase [ERK] 1/2 or PI3-kinase/Akt) during the early min of reperfusion. All of these data have, however, been obtained in adult populations; the question of whether post-conditioning-induced cardioprotection is maintained in aging cohorts is unknown.MethodsIsolated buffer-perfused hearts were obtained from 3- to 4-month-old (adult) and 20- to 24-month-old C57BL/6J mice and subjected to 30 min of ischemia. For each cohort, hearts were randomized to receive standard, abrupt (control) reperfusion, or were post-conditioned with 3 or 6 10-s cycles of stuttered reflow. Primary end points were infarct size, cardiac expression of phospho-Akt, phospho-mitogen-activated protein kinase kinase 1/2 and phospho-ERK 1/2, and expression of mitogen-activated protein kinase-phosphatase-1 (MKP-1: phosphatase purported to play a primary role in ERK dephosphorylation).ResultsIn adult mouse hearts, post-conditioning significantly reduced infarct size via up-regulation of ERK (but not Akt) signaling. In contrast, in the 2-year-old cohort, post-conditioning failed to limit necrosis, possibly a consequence of the deficit in ERK phosphorylation and increased MKP-1 expression seen in old hearts. Indeed, infusion of sodium orthovanadate, a nonspecific MKP inhibitor, attenuated MKP-1 expression and restored the post-conditioned phenotype in old hearts.ConclusionsOld mouse hearts are refractory to infarct size reduction with post-conditioning, possibly because of an age-associated increase in MKP-1 and resultant deficit in ERK phosphorylation.
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