Published Online
on September 19, 2005

A more recent version of this article appeared on September 27, 2005

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Submitted on May 11, 2005
Accepted on June 10, 2005

Role of the Protein Kinase C--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 PhD, Yiru Guo MD, Yanqing Zhu MD, Ou-Li Wang MD, Gregg Rokosh PhD, Robert O. Messing MD, and Roberto Bolli MD^*

From the Institute of Molecular Cardiology (Y.-T.X., Y.G., Y.Z., O.-L.W., G.R., R.B.), University of Louisville, Louisville, Ky, and the Ernest Gallo Clinic and Research Center (R.O.M.), Department of Neurology, University of California at San Francisco, Emeryville, Calif.

^* To whom correspondence should be addressed. E-mail: rbolli{at}louisville.edu.

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)- activity, as determined by both pharmacological and genetic inhibition of PKC.

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 PKC via a PKC-Raf1-MEK1/2-p44/42 MAPK pathway. Furthermore, this is the first report that COX-2 expression in the heart is controlled by PKC. 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 PKC (Ser phosphorylation).

Key words: ischemia • myocardial infarction • signal transduction

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