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PRECLINICAL RESEARCH: AGING AND POST-INFARCT CHANGE

Aging Mouse Hearts Are Refractory to Infarct Size Reduction With Post-Conditioning

Karin Przyklenk, PhD^_*,,,_*, Michelle Maynard^_*, Chad E. Darling, MD^_* and Peter Whittaker, PhD^_*,,,

^_* Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, Massachusetts
Department of Anesthesiology, University of Massachusetts Medical School, Worcester, Massachusetts
Department of Medicine (Cardiology), University of Massachusetts Medical School, Worcester, Massachusetts
Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, Michigan.

Manuscript received September 4, 2007; revised manuscript received November 15, 2007, accepted November 19, 2007.

^_* Reprint requests and correspondence: Dr. Karin Przyklenk, Cardiovascular Research Institute, Wayne State University School of Medicine, 421 East Canfield Avenue, Room 1107.4, Detroit, Michigan 48201. (Email: kprzykle{at}med.wayne.edu).

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.

Abbreviations and Acronyms   ANOVA = analysis of variance   ERK = extracellular-signal regulated kinase   LV = left ventricle/ventricular   MEK = mitogen-activated protein kinase kinase   MKP = mitogen-activated protein kinase phosphatase   PI3 kinase = phosphatidylinositol-3-kinase   STAT3 = signal transducer and activator of transcription 3

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