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Aging mouse hearts are refractory to infarct size reduction with post-conditioning
Karin Przyklenk1, Michelle Maynard, Chad E Darling
1Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA. kprzykle@med.wayne.edu
Journal of the American College of Cardiology
|April 5, 2008
Summary
Post-conditioning effectively reduces heart attack size in adult mice by up-regulating ERK signaling. However, this protective effect is lost in older mice due to increased MKP-1 and reduced ERK phosphorylation.
Area of Science:
- Cardiovascular Research
- Molecular Cardiology
- Aging Biology
Background:
- Post-conditioning limits myocardial infarct size by up-regulating survival kinases like ERK and Akt during reperfusion.
- Previous studies on post-conditioning have exclusively used adult animal models.
- The efficacy of post-conditioning in aging hearts remains largely unexplored.
Purpose of the Study:
- To investigate if the cardioprotective effects of post-conditioning are preserved in aging hearts.
- To determine the molecular mechanisms underlying potential age-related changes in post-conditioning efficacy.
Main Methods:
- Isolated hearts from adult (3-4 months) and aged (20-24 months) C57BL/6J mice were subjected to ischemia and reperfusion.
- Hearts received either standard reperfusion or post-conditioning (3 or 6 cycles of 10-s reflow).
- Infarct size, cardiac phospho-Akt, phospho-MAPKK1/2, phospho-ERK1/2, and MKP-1 expression were assessed.
Main Results:
- Post-conditioning significantly reduced infarct size in adult hearts, associated with ERK but not Akt phosphorylation.
- In aged hearts, post-conditioning failed to reduce infarct size, correlating with reduced ERK phosphorylation and elevated MKP-1.
- Inhibition of MKP-1 with sodium orthovanadate restored the cardioprotective effect of post-conditioning in aged hearts.
Conclusions:
- Aging hearts are refractory to infarct size reduction by post-conditioning.
- This refractoriness may stem from an age-associated increase in MKP-1, which impairs ERK phosphorylation.
- Targeting MKP-1 could potentially restore post-conditioning benefits in older individuals.
