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The activation of p38 alpha, and not p38 beta, mitogen-activated protein kinase is required for ischemic

Pierre Sicard1, James E Clark, Sebastien Jacquet

  • 1King's College London BHF Centre, Cardiovascular Division, The Rayne Institute, St. Thomas' Hospital, London SE1 7EH, UK.

Journal of Molecular and Cellular Cardiology
|March 2, 2010
PubMed

Insights

Pharmacological inhibition of p38 kinases prevents heart conditioning, but isoform-specific studies reveal p38 alpha activation is crucial for this protective effect. This finding challenges targeted therapeutic strategies for myocardial injury.

Area of Science:

  • Cardiovascular Research
  • Molecular Biology
  • Pharmacology

Background:

  • Pharmacological inhibition of p38 mitogen-activated protein kinases (p38s) is known to prevent ischemic conditioning.
  • Existing inhibitors lack isoform specificity and have off-target effects, complicating the understanding of p38 alpha and p38 beta roles.
  • p38 alpha is implicated in aggravating myocardial injury, while p38 beta is thought to reduce it.

Purpose of the Study:

  • To investigate the specific roles of p38 alpha and p38 beta isoforms in ischemic preconditioning using a chemical genetic approach.
  • To determine whether p38 alpha or p38 beta activation is necessary for the protective effects of ischemic preconditioning.

Main Methods:

  • Utilized genetically modified mice (DR alpha and DR beta) with targeted gatekeeper mutations to confer resistance to the inhibitor SB203580.
  • Isolated, perfused mouse hearts underwent ischemic preconditioning followed by global ischemia and reperfusion.
  • Assessed the effects of SB203580 on myocardial infarction and downstream substrate phosphorylation in wild-type, DR alpha, and DR beta hearts.

Main Results:

  • SB203580 abolished the protective effects of preconditioning and downstream substrate phosphorylation in wild-type and DR beta hearts.
  • These effects were not observed in DR alpha hearts, indicating p38 alpha is essential for SB203580's action.
  • Ischemic preconditioning remained unaltered in p38 beta null hearts.

Conclusions:

  • Contrary to expectations, p38 alpha activation, not p38 beta, is necessary for ischemic preconditioning.
  • Since p38 alpha also contributes to lethal myocardial injury, isoform-selective inhibition strategies may not solely prevent harmful consequences.
  • This study highlights the complex and isoform-dependent roles of p38 kinases in cardiac protection and injury.

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