Ischemic preconditioning attenuates mitochondrial localization of PTEN induced by ischemia-reperfusion

Lingyun Zu, Xiaoxu Zheng, Bing Wang, Nirmal Parajuli, Charles Steenbergen, Lewis C. Becker, Zheqing P. Cai

Research output: Contribution to journalArticlepeer-review

Abstract

Although the induction of myocyte apoptosis by ischemia-reperfusion (I/R) is attenuated by ischemic preconditioning (IPC), the underlying mechanism is not fully understood. Phosphatase and tensin homologs deleted on chromosome 10 (PTEN) promotes apoptosis through Akt-dependent and -independent mechanisms. We tested the hypothesis that IPC attenuates the mitochondrial localization of PTEN in the myocardium induced by I/R. Isolated hearts from wild-type mice were exposed to IPC or normal perfusion followed by 30 min of ischemia and reperfusion. IPC attenuated myocardial infarct size and apoptosis after I/R. Heart fractionation showed that mitochondrial PTEN and Bax protein levels and the physical association between them were increased by 30 min of I/R and that IPC attenuated all of these effects of I/R. Muscle-specific PTEN knockout decreased mitochondrial Bax protein levels in the reperfused myocardium and increased cell survival. To determine whether PTEN relocalization to mitochondria was influenced by I/R-induced production of ROS, hearts were perfused with N-acetylcysteine (NAC) to scavenge ROS or H2O2 to mimic I/Rinduced ROS. Mitochondrial PTEN protein levels were decreased by NAC and increased by H2O2. PTEN protein overexpression was generated in mouse hearts by adenoviral gene transfer. PTEN overexpression increased mitochondrial PTEN and Bax protein levels and ROS production, whereas muscle-specific PTEN knockout produced the opposite effects. In conclusion, myocardial I/R causes PTEN localization to the mitochondria, related to the generation of ROS; IPC attenuates the mitochondrial localization of PTEN after I/R, potentially inhibiting the translocation of Bax to the mitochondria and resulting in improved cell viability.

Original languageEnglish (US)
Pages (from-to)H2177-H2186
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume300
Issue number6
DOIs
StatePublished - Jun 2011

Keywords

  • Apoptosis
  • Bax
  • Phosphatase and tensin homologs deleted on chromosome 10
  • Reperfusion injury

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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