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

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• 作者：Karol Szczepanek ; Aijun Xu ; Ying Hu ; Jeremy Thompson…
• 关键词：Myocardial infarction ; Reactive oxygen species ; Necrosis ; Apoptosis ; Mitochondrial permeability transition
• 刊名：Basic Research in Cardiology
• 出版年：2015
• 出版时间：November 2015
• 年：2015
• 卷：110
• 期：6
• 全文大小：653 KB
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• 作者单位：Karol Szczepanek (1)
  Aijun Xu (1) (3)
  Ying Hu (1)
  Jeremy Thompson (1)
  Jun He (1)
  Andrew C. Larner (4)
  Fadi N. Salloum (1)
  Qun Chen (1)
  Edward J. Lesnefsky (1) (2) (4)
  
  1. Division of Cardiology, Department of Internal Medicine and Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, 23298, USA
  3. Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
  4. Department of Biochemistry and Molecular Biology, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA
  2. Medical Service McGuire Veterans Affairs Medical Center, McGuire VAMC Cardiology 111(J), Richmond, VA, 23249, USA
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Cardiology
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1435-1803

文摘

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. Keywords Myocardial infarction Reactive oxygen species Necrosis Apoptosis Mitochondrial permeability transition