Aging mouse hearts are refractory to infarct size reduction with post-conditioning

J Am Coll Cardiol. 2008 Apr 8;51(14):1393-8. doi: 10.1016/j.jacc.2007.11.070.


Objectives: 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging*
  • Animals
  • Heart Ventricles / physiopathology
  • Hypertrophy, Left Ventricular / etiology
  • Hypertrophy, Left Ventricular / prevention & control
  • MAP Kinase Signaling System*
  • Mice
  • Mice, Inbred C57BL
  • Myocardial Infarction / complications
  • Myocardial Infarction / enzymology
  • Myocardial Infarction / pathology
  • Myocardial Infarction / physiopathology*
  • Myocardial Reperfusion*
  • Myocardium / enzymology
  • Myocardium / pathology*
  • Phenotype
  • Random Allocation
  • Time Factors
  • Up-Regulation