Inhibition of permeability transition pore opening by mitochondrial STAT3 and its role in myocardial ischemia/reperfusion

Basic Res Cardiol. 2010 Nov;105(6):771-85. doi: 10.1007/s00395-010-0124-1. Epub 2010 Oct 20.

Abstract

The signal transducer and activator of transcription 3 (STAT3) contributes to cardioprotection by ischemic pre- and postconditioning. Mitochondria are central elements of cardioprotective signaling, most likely by delaying mitochondrial permeability transition pore (MPTP) opening, and STAT3 has recently been identified in mitochondria. We now characterized the mitochondrial localization of STAT3 and its impact on respiration and MPTP opening. STAT3 was mainly present in the matrix of subsarcolemmal and interfibrillar cardiomyocyte mitochondria. STAT1, but not STAT5 was also detected in mitochondria under physiological conditions. ADP-stimulated respiration was reduced in mitochondria from mice with a cardiomyocyte-specific deletion of STAT3 (STAT3-KO) versus wildtypes and in rat mitochondria treated with the STAT3 inhibitor Stattic (STAT3 inhibitory compound, 6-Nitrobenzo[b]thiophene 1,1-dioxide). Mitochondria from STAT3-KO mice and Stattic-treated rat mitochondria tolerated less calcium until MPTP opening occurred. STAT3 co-immunoprecipitated with cyclophilin D, the target of the cardioprotective agent and MPTP inhibitor cyclosporine A (CsA). However, CsA reduced infarct size to a similar extent in wildtype and STAT3-KO mice in vivo. Thus, STAT3 possibly contributes to cardioprotection by stimulation of respiration and inhibition of MPTP opening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Diphosphate / metabolism
  • Animals
  • Calcium / metabolism
  • Cell Respiration
  • Cyclic S-Oxides / pharmacology
  • Cyclophilin D
  • Cyclophilins / metabolism
  • Cyclosporine / pharmacology
  • Disease Models, Animal
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria, Heart / drug effects
  • Mitochondria, Heart / metabolism*
  • Mitochondria, Heart / pathology
  • Mitochondrial Membrane Transport Proteins / antagonists & inhibitors
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Myocardial Reperfusion Injury / metabolism*
  • Myocardial Reperfusion Injury / pathology
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Oxygen Consumption
  • Phosphorylation
  • Rats
  • Rats, Inbred Lew
  • STAT3 Transcription Factor / antagonists & inhibitors
  • STAT3 Transcription Factor / deficiency
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*

Substances

  • Cyclic S-Oxides
  • Cyclophilin D
  • Mitochondrial Membrane Transport Proteins
  • PPIF protein, mouse
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Stat3 protein, rat
  • mitochondrial permeability transition pore
  • stattic
  • Adenosine Diphosphate
  • Cyclosporine
  • Cyclophilins
  • Calcium