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An obligatory role of STAT1 in the upregulation of cardioprotective proteins and delayed cardioprotection in ischemic preconditioning
Author(s) -
Stein Adam Barnett,
Bolli Roberto,
Guo Yiru,
Zhu Yanqing,
Wang OuLi,
Rokosh Gregg,
Xuan YuTing
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1376-a
Subject(s) - cardioprotection , stat1 , downregulation and upregulation , stat3 , phosphorylation , ischemic preconditioning , chemistry , in vivo , pharmacology , cancer research , medicine , ischemia , biology , biochemistry , gene , microbiology and biotechnology
Studies with the JAK‐STAT inhibitor AG‐490 suggest that activation of STAT1 and STAT3 is necessary for the delayed protection afforded by ischemic preconditioning (PC). However, the individual role of STAT1 in late PC‐induced cardioprotection remains unclear. We used STAT1 −/− mice to investigate the role of STAT1 in mediating the protective effects of ischemic PC and the expression of cardioprotective proteins (iNOS, COX‐2, and HO‐1). In wild‐type mice, ischemic PC induced phosphorylation of STAT1 (pTyr(701) and pSer(727)) and increased STAT‐DNA binding activity 30 min later; 24 h later, PC increased expression of iNOS, COX‐2, and HO‐1, and reduced infarct size. The expression and phosphorylation of STAT1 was eliminated in STAT1 −/− mice. Deletion of STAT1 did not affect the expression or the phosphorylation of STAT3. STAT1 deletion inhibited the PC‐induced increase in STAT‐DNA binding activity, blocked the PC‐induced upregulation of iNOS, COX‐2, and HO‐1, and attenuated the protection of PC against myocardial infarction. We conclude that STAT1 activates a pro‐survival mechanism that protects against cardiac cell death during late PC. In contrast to previous in vitro studies, our results in vivo demonstrate that STAT1 plays an obligatory role in PC‐induced upregulation of cardioprotective proteins and in the delayed cardioprotection afforded by ischemic PC. National AHA 0575035N and NIH R01 HL‐65660 and P01 HL‐78825