title: Aging mouse hearts are refractory to infarct size reduction with post-conditioning.
abstract: OBJECTIVE
  Our aim was to establish whether the efficacy of post-conditioning is maintained in aging hearts.
  
  
  BACKGROUND
  Post-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.
  
  
  METHODS
  Isolated 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).
  
  
  RESULTS
  In 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.
  
  
  CONCLUSIONS
  Old 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.
authors.affiliation: Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA. kprzykle@med.wayne.edu
authors.forename: Karin
authors.initials: K
authors.lastname: Przyklenk
authors.forename: Michelle
authors.initials: M
authors.lastname: Maynard
authors.forename: Chad E
authors.initials: CE
authors.lastname: Darling
authors.forename: Peter
authors.initials: P
authors.lastname: Whittaker
mesh_terms: D000375:Aging; D000818:Animals; D006352:Heart Ventricles / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000517:prevention & control; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000150:complications / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000201:enzymology / Q000473:pathology*; D010641:Phenotype; D011897:Random Allocation; D013997:Time Factors; D015854:Up-Regulation