Cardioprotective function of mitochondrial-targeted and transcriptionally inactive STAT3 against ischemia and reperfusion injury

Karol Szczepanek, Aijun Xu, Ying Hu, Jeremy Thompson, Jun He, Andrew C. Larner, Fadi N. Salloum, Qun Chen, Edward J. Lesnefsky

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that contributes a crucial role in protection against ischemia (ISC)-reperfusion (REP) injury by driving expression of anti-apoptotic and anti-oxidant genes. STAT3 is also present in the mitochondria, where it modulates the activity of the electron transport chain (ETC) and the permeability transition pore. Transgenic mice that overexpress a mitochondrial-targeted, transcriptionally inactive STAT3 in cardiomyocytes (MLS-STAT3E mice) exhibit a persistent, partial blockade of electron transfer through complex I that uniquely did not lead to tissue dysfunction at baseline, yet increased mitochondrial ischemic tolerance. The direct contribution of non-transcriptional, mitochondria-localized STAT3 to protection during ISC-REP remains to be established. We hypothesized that the enhanced mitochondrial tolerance to ischemia present in MLS-STAT3E mice would decrease cardiac injury during ISC-REP. In the isolated buffer-perfused heart model, MLS-STAT3E hearts exhibit a decreased infarct size compared to non-transgenic littermate hearts. Contractile recovery, expressed as a percent of LV developed pressure before ISC, is improved in MLS-STAT3E mice. Mitochondria isolated at the end of 60 min. of REP from MLS-STAT3E hearts show attenuated ROS release. The partial and persistent blockade of complex I present in MLS-STAT3E mice decreases cardiac injury during REP, in part via a persistent decrease in ROS production and attenuation of mitochondrial permeability transition pore opening at the onset of REP. In vivo, MLS-STAT3E hearts exhibit substantially higher postoperative survival rate and a substantial decrease in myocardial infarct size. STAT3 mediates cardioprotection not only via canonical action as a transcription factor, but also as a modulator of ETC activity directly in the mitochondria.

Original languageEnglish (US)
Article number53
JournalBasic Research in Cardiology
Volume110
Issue number6
DOIs
StatePublished - Nov 14 2015

Keywords

  • Apoptosis
  • Mitochondrial permeability transition
  • Myocardial infarction
  • Necrosis
  • Reactive oxygen species

ASJC Scopus subject areas

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

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