title: lschemic preconditioning in pigs: a causal role for signal transducer and activator of transcription 3.
abstract: Ischemic preconditioning (IPC), i.e., brief episodes of nonlethal myocardial ischemia-reperfusion (I/R) before sustained ischemia with subsequent reperfusion, reduces infarct size in all species tested so far, including humans. In rodents, the cardioprotective signal transduction causally involves an activation of Akt, ERK1/2, and STAT3. However, there are apparent species differences in the signal transduction between rodents and larger mammals such as pigs, where data on IPC's signal transduction are inconsistent for Akt and ERK1/2. The role of STAT3 has not yet been analyzed. Pigs were subjected to 60 min of left anterior descending coronary artery occlusion and 180 min of reperfusion without or with IPC (2 cycles of 3-min occlusion separated by 2 min of reperfusion 15 min before sustained I/R). Infarct size was analyzed by triphenyl tetrazolium chloride staining, and Akt, ERK1/2, and STAT3 phosphorylation was quantified in myocardial biopsies taken at baseline and early reperfusion. AG490 was used to block the STAT3 signaling pathway. IPC reduced infarct size (%area at risk; mean ± SE, I/R, 45 ± 3 vs. IPC, 18 ± 3,P< 0.05). Akt and ERK1/2 phosphorylation was increased at early reperfusion without and with IPC. In contrast, STAT3 phosphorylation at early reperfusion was only increased with IPC (%baseline; mean ± SE, I/R, 126 ± 29 vs. IPC, 408 ± 147,P< 0.05). AG490 prevented the IPC-related increase of STAT3 phosphorylation at reperfusion (%baseline; mean ± SE, 82 ± 12) and abolished IPC's cardioprotection (%area at risk; mean ± SE, 35 ± 4). In pigs, increased phosphorylation of STAT3 is causally involved, whereas Akt and ERK1/2 seem to play no role in IPC's cardioprotection.NEW & NOTEWORTHYIn pig hearts in situ, ischemic preconditioning (IPC) causally involves increased phosphorylation of STAT3, whereas Akt and ERK1/2 play no role for cardioprotection. The cardioprotective signal transduction of IPC is similar to that of ischemic postconditioning and remote IPC in pigs.
authors.affiliation: Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen, Medical School, Essen, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Gent
authors.affiliation: Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen, Medical School, Essen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Skyschally
authors.affiliation: Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen, Medical School, Essen, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Kleinbongard
authors.affiliation: Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen, Medical School, Essen, Germany gerd.heusch@uk-essen.de.
authors.forename: Gerd
authors.initials: G
authors.lastname: Heusch
mesh_terms: D000818:Animals; D001831:Body Temperature; D006439:Hemodynamics; D019157:Ischemic Preconditioning, Myocardial; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control; D051058:Oncogene Protein v-akt / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D034421:Sus scrofa; D013552:Swine; D013556:Swine, Miniature; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D050796:STAT3 Transcription Factor; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D053614:Janus Kinase 2; D051058:Oncogene Protein v-akt
keywords: STAT3; ischemic preconditioning; pigs