title: Cardioprotective function of mitochondrial-targeted and transcriptionally inactive STAT3 against ischemia and reperfusion injury.
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.
authors.affiliation: Division of Cardiology, Department of Internal Medicine and Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, 23298, USA.
authors.forename: Karol
authors.initials: K
authors.lastname: Szczepanek
authors.affiliation: Division of Cardiology, Department of Internal Medicine and Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, 23298, USA.|Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Aijun
authors.initials: A
authors.lastname: Xu
authors.affiliation: Division of Cardiology, Department of Internal Medicine and Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, 23298, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Division of Cardiology, Department of Internal Medicine and Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, 23298, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Thompson
authors.affiliation: Division of Cardiology, Department of Internal Medicine and Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, 23298, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Biochemistry and Molecular Biology, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Larner
authors.affiliation: Division of Cardiology, Department of Internal Medicine and Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, 23298, USA.
authors.forename: Fadi N
authors.initials: FN
authors.lastname: Salloum
authors.affiliation: Division of Cardiology, Department of Internal Medicine and Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, 23298, USA.
authors.forename: Qun
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Division of Cardiology, Department of Internal Medicine and Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, 23298, USA. edward.lesnefsky@vcuhealth.org.|Medical Service McGuire Veterans Affairs Medical Center, McGuire VAMC Cardiology 111(J), Richmond, VA, 23249, USA. edward.lesnefsky@vcuhealth.org.|Department of Biochemistry and Molecular Biology, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA. edward.lesnefsky@vcuhealth.org.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Lesnefsky
mesh_terms: D000818:Animals; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000401:mortality / Q000517:prevention & control; D017382:Reactive Oxygen Species / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse
keywords: Apoptosis; Mitochondrial permeability transition; Myocardial infarction; Necrosis; Reactive oxygen species