Ischemic preconditioning inhibits mitochondrial permeability transition pore opening through the PTEN/PDE4 signaling pathway

Xiaoxu Zheng, Lingyun Zu, Lewis Becker, Zheqing P. Cai

Research output: Contribution to journalArticlepeer-review

Abstract

Objectives: Ischemic preconditioning (IPC) induces cardioprotection against ischemia-reperfusion (IR) injury by inhibiting the mitochondrial permeability transition pore (mPTP). Here, we tested the hypothesis that IPC-induced cardioprotection is mediated by the phosphatase PTEN and PDE4 (phosphodiesterase 4).

Methods: Isolated hearts from wildtype mice (WT, n = 110) and myocyte-specific PTEN-knockout mice (PKO, n = 94) were exposed to IPC or control conditions followed by IR. Subcellular fractionation was performed by sucrose gradient ultracentrifugation.

Results: IPC limited myocardial infarct size (IS) in WT mice. The PDE4 inhibitor rolipram abolished the protective effect of IPC. However, small IS was found in PKO hearts after IR, and IPC did not decrease IS but enlarged it in PKO hearts. IPC promoted PDE4D localization to caveolin-3-enriched fractions in WT mice by increasing Akt levels at the caveolae. In PKO hearts, basal PDE4D levels were elevated at the caveolae, and IPC decreased PDE4D levels. Consistent with the subcellular PDE4D protein levels and its activity, elevation in intracellular Ca2+ levels in the ischemic heart and opening of mPTP after IR were inhibited by IPC in WT mice, but not by IPC in PKO mice.

Conclusions: IPC inhibits mPTP opening by regulating the PTEN/PDE4 signaling pathway.

Original languageEnglish (US)
Pages (from-to)163-173
Number of pages11
JournalCardiology (Switzerland)
Volume129
Issue number3
DOIs
StatePublished - Nov 19 2014

Keywords

  • Akt
  • Ischemic preconditioning
  • Mitochondrial permeability transition pore
  • PDE4
  • PTEN

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Pharmacology (medical)

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