Role of the protein kinase C-ε-Raf-1-MEK-1/2-p44/42 MAPK signaling cascade in the activation of signal transducers and activators of transcription 1 and 3 and induction of cyclooxygenase-2 after ischemic preconditioning

Yu Ting Xuan, Yiru Guo, Yanqing Zhu, Ou Li Wang, Gregg Rokosh, Robert O. Messing, Roberto Bolli

Research output: Contribution to journalArticle

Abstract

Background - Although Janus kinase (JAK)-mediated Tyr phosphorylation of signal transducers and activators of transcription (STAT) 1 and 3 is essential for the upregulation of cyclooxygenase-2 (COX-2) and the cardioprotection of late preconditioning (PC), the role of Ser phosphorylation of STAT1 and STAT3 in late PC and the upstream signaling mechanisms responsible for mediating Ser phosphorylation of STAT1 and STAT3 remain unknown. Methods and Results - In mice preconditioned with six 4-minute coronary occlusion/4-minute reperfusion cycles, we found that (1) ischemic PC activates the Raf1-mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase kinase (MEK) 1/2-p44/42 MAPK signaling pathway, induces phosphorylation of STAT1 and STAT3 on the Ser-727 residue, and upregulates COX-2 expression; (2) pSer-STAT1 and pSer-STAT3 form complexes with pTyr-p44/42 MAPKs in preconditioned myocardium, supporting the concept that Ser phosphorylation of these 2 factors is mediated by activated p44/42 MAPKs; and (3) activation of the Raf-1-MEK-1/2-p44/42 MAPK-pSer-STAT1/3 pathway and induction of COX-2 during ischemic PC are dependent on protein kinase C (PKC)-ε activity, as determined by both pharmacological and genetic inhibition of PKCε. Conclusions - To our knowledge, this is the first study to demonstrate that ischemic PC causes Ser phosphorylation of STAT1 and STAT3 and that this event is governed by PKCε via a PKCε-Raf1-MEK1/2-p44/42 MAPK pathway. Furthermore, this is the first report that COX-2 expression in the heart is controlled by PKCε. Together with our previous findings, the present study implies that STAT-dependent transcription of the genes responsible for ischemic PC is modulated by a dual signaling mechanism that involves both JAK1/2 (Tyr phosphorylation) and PKCε (Ser phosphorylation).

Original languageEnglish (US)
Pages (from-to)1971-1978
Number of pages8
JournalCirculation
Volume112
Issue number13
DOIs
StatePublished - Sep 27 2005
Externally publishedYes

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Proto-Oncogene Proteins c-raf
STAT1 Transcription Factor
STAT3 Transcription Factor
Ischemic Preconditioning
Mitogen-Activated Protein Kinase Kinases
Cyclooxygenase 2
Mitogen-Activated Protein Kinases
Protein Kinase C
Phosphorylation
Mitogen-Activated Protein Kinase 3
MAP Kinase Kinase Kinase 2
MAP Kinase Kinase Kinase 1
Up-Regulation
Janus Kinases
Coronary Occlusion
Extracellular Signal-Regulated MAP Kinases
Transducers
Reperfusion
Myocardium
Pharmacology

Keywords

  • Ischemia
  • Myocardial infarction
  • Signal transduction

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Role of the protein kinase C-ε-Raf-1-MEK-1/2-p44/42 MAPK signaling cascade in the activation of signal transducers and activators of transcription 1 and 3 and induction of cyclooxygenase-2 after ischemic preconditioning. / Xuan, Yu Ting; Guo, Yiru; Zhu, Yanqing; Wang, Ou Li; Rokosh, Gregg; Messing, Robert O.; Bolli, Roberto.

In: Circulation, Vol. 112, No. 13, 27.09.2005, p. 1971-1978.

Research output: Contribution to journalArticle

Xuan, Yu Ting ; Guo, Yiru ; Zhu, Yanqing ; Wang, Ou Li ; Rokosh, Gregg ; Messing, Robert O. ; Bolli, Roberto. / Role of the protein kinase C-ε-Raf-1-MEK-1/2-p44/42 MAPK signaling cascade in the activation of signal transducers and activators of transcription 1 and 3 and induction of cyclooxygenase-2 after ischemic preconditioning. In: Circulation. 2005 ; Vol. 112, No. 13. pp. 1971-1978.
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T1 - Role of the protein kinase C-ε-Raf-1-MEK-1/2-p44/42 MAPK signaling cascade in the activation of signal transducers and activators of transcription 1 and 3 and induction of cyclooxygenase-2 after ischemic preconditioning

AU - Xuan, Yu Ting

AU - Guo, Yiru

AU - Zhu, Yanqing

AU - Wang, Ou Li

AU - Rokosh, Gregg

AU - Messing, Robert O.

AU - Bolli, Roberto

PY - 2005/9/27

Y1 - 2005/9/27

N2 - Background - Although Janus kinase (JAK)-mediated Tyr phosphorylation of signal transducers and activators of transcription (STAT) 1 and 3 is essential for the upregulation of cyclooxygenase-2 (COX-2) and the cardioprotection of late preconditioning (PC), the role of Ser phosphorylation of STAT1 and STAT3 in late PC and the upstream signaling mechanisms responsible for mediating Ser phosphorylation of STAT1 and STAT3 remain unknown. Methods and Results - In mice preconditioned with six 4-minute coronary occlusion/4-minute reperfusion cycles, we found that (1) ischemic PC activates the Raf1-mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase kinase (MEK) 1/2-p44/42 MAPK signaling pathway, induces phosphorylation of STAT1 and STAT3 on the Ser-727 residue, and upregulates COX-2 expression; (2) pSer-STAT1 and pSer-STAT3 form complexes with pTyr-p44/42 MAPKs in preconditioned myocardium, supporting the concept that Ser phosphorylation of these 2 factors is mediated by activated p44/42 MAPKs; and (3) activation of the Raf-1-MEK-1/2-p44/42 MAPK-pSer-STAT1/3 pathway and induction of COX-2 during ischemic PC are dependent on protein kinase C (PKC)-ε activity, as determined by both pharmacological and genetic inhibition of PKCε. Conclusions - To our knowledge, this is the first study to demonstrate that ischemic PC causes Ser phosphorylation of STAT1 and STAT3 and that this event is governed by PKCε via a PKCε-Raf1-MEK1/2-p44/42 MAPK pathway. Furthermore, this is the first report that COX-2 expression in the heart is controlled by PKCε. Together with our previous findings, the present study implies that STAT-dependent transcription of the genes responsible for ischemic PC is modulated by a dual signaling mechanism that involves both JAK1/2 (Tyr phosphorylation) and PKCε (Ser phosphorylation).

AB - Background - Although Janus kinase (JAK)-mediated Tyr phosphorylation of signal transducers and activators of transcription (STAT) 1 and 3 is essential for the upregulation of cyclooxygenase-2 (COX-2) and the cardioprotection of late preconditioning (PC), the role of Ser phosphorylation of STAT1 and STAT3 in late PC and the upstream signaling mechanisms responsible for mediating Ser phosphorylation of STAT1 and STAT3 remain unknown. Methods and Results - In mice preconditioned with six 4-minute coronary occlusion/4-minute reperfusion cycles, we found that (1) ischemic PC activates the Raf1-mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase kinase (MEK) 1/2-p44/42 MAPK signaling pathway, induces phosphorylation of STAT1 and STAT3 on the Ser-727 residue, and upregulates COX-2 expression; (2) pSer-STAT1 and pSer-STAT3 form complexes with pTyr-p44/42 MAPKs in preconditioned myocardium, supporting the concept that Ser phosphorylation of these 2 factors is mediated by activated p44/42 MAPKs; and (3) activation of the Raf-1-MEK-1/2-p44/42 MAPK-pSer-STAT1/3 pathway and induction of COX-2 during ischemic PC are dependent on protein kinase C (PKC)-ε activity, as determined by both pharmacological and genetic inhibition of PKCε. Conclusions - To our knowledge, this is the first study to demonstrate that ischemic PC causes Ser phosphorylation of STAT1 and STAT3 and that this event is governed by PKCε via a PKCε-Raf1-MEK1/2-p44/42 MAPK pathway. Furthermore, this is the first report that COX-2 expression in the heart is controlled by PKCε. Together with our previous findings, the present study implies that STAT-dependent transcription of the genes responsible for ischemic PC is modulated by a dual signaling mechanism that involves both JAK1/2 (Tyr phosphorylation) and PKCε (Ser phosphorylation).

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KW - Myocardial infarction

KW - Signal transduction

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