title: STAT signaling in ischemic heart: a role of STAT5A in ischemic preconditioning.
abstract: We recently demonstrated that ischemic preconditioning (PC) induced by cyclic episodes of short duration of ischemia and reperfusion potentiates a signal transduction cascade involving Janus kinase (JAK) 2 and signal transducer and activator of transcription 3 (STAT3). A rapid activation of JAK and several STATs, including STAT3, STAT5A, and STAT6 also occurred during myocardial ischemia and reperfusion. This study sought to examine whether STAT5A and STAT6 were also involved in PC. Two different animal models were used: isolated perfused working rat hearts and STAT5A and STAT6 knockout mouse hearts. The results of our study indicated phosphorylation of STAT 5A and STAT6 in the preconditioned myocardium. Tyrphostin AG490, a JAK2 inhibitor, or 4-amino-5-(4-methylphenyl)-7-(t-butyl)-pyrazolo-3,4-d-pyrimidine (PPI), a Src kinase blocker, blocked STAT5A phosphorylation, whereas STAT6 phosphorylation was blocked only with tyrphostin. As expected, significant cardioprotection was achieved in the preconditioned heart as evidenced by reduced myocardial infarct size and decreased number of apoptotic cardiomyocytes. PC-mediated cardioprotection was partially abolished when hearts were pretreated with tyrphostin, PPI, or LY-294002, a phosphatidylinositol (PI)-3 kinase inhibitor. Studies with STAT5A and STAT6 knockout mouse hearts revealed that STAT6 knockout mouse hearts, and not STAT5A knockout mouse hearts, were resistant to myocardial ischemia-reperfusion injury. The hearts from STAT5A knockout mice could not be preconditioned, whereas those from STAT6 knockout mice were easily preconditioned. The results of the present study demonstrate that STAT5A, and not STAT6, plays a role in ischemic PC. For the first time, the results also indicated a role of Src kinase pathway in STAT5A PC and PI-3 kinase-Akt pathways appear to be the downstream regulator for STAT5A-STAT6 signaling pathway.
authors.affiliation: Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, CT 06030-1110, USA.
authors.forename: Genbu
authors.initials: G
authors.lastname: Yamaura
authors.forename: Tibor
authors.initials: T
authors.lastname: Turoczi
authors.forename: Fumio
authors.initials: F
authors.lastname: Yamamoto
authors.forename: M A Q
authors.initials: MA
authors.lastname: Siddqui
authors.forename: Nilanjana
authors.initials: N
authors.lastname: Maulik
authors.forename: Dipak K
authors.initials: DK
authors.lastname: Das
mesh_terms: D000818:Animals; D017209:Apoptosis; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019157:Ischemic Preconditioning, Myocardial; D053614:Janus Kinase 2; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008894:Milk Proteins; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D050799:STAT5 Transcription Factor; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D053614:Janus Kinase 2; D008894:Milk Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D050799:STAT5 Transcription Factor; D050800:STAT6 Transcription Factor; D015534:Trans-Activators; D019061:src-Family Kinases; C494093:Stat5a protein, mouse; C494094:Stat5a protein, rat; C494100:Stat6 protein, mouse; C507926:Jak2 protein, mouse; C507927:Jak2 protein, rat; C494920:Akt1 protein, rat