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Heart and Vessels

, Volume 13, Issue 4, pp 199–208 | Cite as

Involvement of gp130-mediated signaling in pressure overload-induced activation of the JAK/STAT pathway in rodent heart

  • Jing Pan
  • Keiichi Fukuda
  • Hiroaki Kodama
  • Motoaki Sano
  • Toshiyuki Takahashi
  • Shinji Makino
  • Takahiro Kato
  • Tomohiro Manabe
  • Shingo Hori
  • Satoshi Ogawa
Originals

Summary

Previously, we showed that the JAK/STAT pathway was activated in pressure-overloaded rat heart, and that angiotensin II was partially involved in this activation. The present study was designed to investigate whether gp130-mediated signaling is involved in this activation, and if so, which interleukin (IL)-6 family cytokine is involved. Pressure overload was produced by ligation of the abdominal aorta of Wistar rats or ICR mice. IP-Western blot was performed to detect tyrosine phosphorylation of STATs, gp130, and the association of gp130 with JAK kinases. The serum concentration of IL-6 was measured by enzyme-linked immunosorbent assay. Expression of IL-6, IL-11, leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), oncostatin M (OSM), and cardiotrophin-1 (CT-1) mRNA was quantitated. After pressure overload, rapid phosphorylation of STAT1 and STAT3 was observed at 5min, STAT1 was rephosphorylated at 60min, and intense phosphorylation of STAT3 was observed at 60min. Both the phosphorylation of gp130 and the association of gp130 with JAK1 and JAK2 were increased after pressure overload. IL-6 was significantly increased by two-fold in the pressure-overloaded rats. Only CT-1 mRNA expression could be detected by Northern blot, and it increased after pressure overload. Reverse transcription-polymerase chain reaction revealed that IL-6 mRNA expression was increased 9.5-fold. IL-11, LIF, CNTF, and OSM expression were unaffected by pressure overload. These results suggested that gp130mediated signaling was involved in the pressure overload-induced activation of the JAK/STAT pathway, and that IL-6 and CT-1 might be involved in this activation.

Key words

Myocardial hypertrophy Pressure overload gp130 JAK/STAT pathway Cardiotrophin-1 

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References

  1. 1.
    Darnell JE Jr, Kerr IM, Stark GR (1994) Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264:1415–1421Google Scholar
  2. 2.
    Schindler C, Darnell JE (1995) Transcriptional responses to polypeptide ligands: the JAK/STAT pathway. Annu Rev Biochem 64:621–651Google Scholar
  3. 3.
    Marrero MB, Schieffer B, Paxton WG, Heerdt L, Berk BC, Delafontaine P, Bernstein KE (1995) Direct stimulation of Jak/STAT pathway by the angiotensin II AT1 receptor. Nature 375:247–250Google Scholar
  4. 4.
    Robledo O, Fourcin M, Chevalier S, Guillet C, Auguste P, Pouplard-Barthelaix A, Pennica D, Gascan H (1997) Signaling of the cardiotrophin-1 receptor. Evidence for a third receptor component. J Biol Chem 272:4855–4863Google Scholar
  5. 5.
    Sheng Z, Knowlton K, Chen J, Hoshijima M, Brown JH, Chien KR (1997) Cardiotrophin-1 (CT-1) inhibition of cardiac myocyte apoptosis via a mitogen-activated protein kinase-dependent pathway. J Biol Chem 272:5783–5791Google Scholar
  6. 6.
    Pan J, Fukuda K, Kodama H, Makino S, Takahashi T, Sano M, Hori S, Ogawa S (1997) Role of angiotensin II in activation of the JAK/STAT pathway induced by acute pressure-overload in the rat heart. Circ Res 81:611–617Google Scholar
  7. 7.
    Kodama H, Fukuda K, Pan J, Makino S, Sano M, Takahashi T, Hori S, Ogawa S (1998) Biphasic activation of the JAK/STAT pathway by angiotensin II in rat cardiomyocytes. Circ Res 82:244–250Google Scholar
  8. 8.
    Mcwhinney CD, Hunt RA, Conrad KM, Dostal DE, Baker KM (1997) The type I angiotensin II receptor couples to Stat1 and Stat3 activation through Jak2 kinase in neonatal rat cardiac myocytes. J Mol Cell Cardiol 29:2513–2524Google Scholar
  9. 9.
    Kodama H, Fukuda K, Pan J, Makino S, Baba A, Hori S, Ogawa S (1997) Leukemia inhibitory factor, a potent cardiac hypertrophic cytokine, Activates the JAK/STAT pathway in rat cardiomyocytes. Circ Res 81:656–663Google Scholar
  10. 10.
    Kunisada K, Hirota H, Fujio Y, Matsui H, Tani Y, Yamauchi-Takihara K, Kishimoto T (1996) Activation of JAK-STAT and MAP kinases by leukemia inhibitory factor through gp130 in cardiac myocytes. Circulation 94:2626–2632Google Scholar
  11. 11.
    Narazaki M, Witthuhn BA, Yoshida K, Silvennoinen O, Yasukawa K, Ihle JN, Kishimoto T, Taga T (1994) Activation of JAK2 kinase mediated by the interleukin 6 signal transducer gp130. Proc Natl Acad Sci USA 91:2285–2289Google Scholar
  12. 12.
    Stahl N, Boulton TG, Farruggella T, Ip NY, Davis S, Witthuhn BA, Quelle FW, Silvennoinen O, Barbieri G, Pellegrini S, Ihle JN, Yancopoulos GD (1994) Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components. Science 263:92–95Google Scholar
  13. 13.
    Wang Y, Fuller GM (1995) Interleukin-6 and ciliary neurotrophic factor trigger janus kinase activation and early gene response in rat hepatocytes. Gene 162:285–289Google Scholar
  14. 14.
    Yoshida K, Taga T, Saito M, Suematsu S, Kumanogoh A, Tanaka T, Fujiwara H, Hirata M, Yamagami T, Nakahata T, Hirabayashi T, Yoneda Y, Tanaka K, Wang WZ, Mori C (1996) Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematological disorders. Proc Natl Acad Sci USA 93:407–411Google Scholar
  15. 15.
    Hirota H, Yoshida K, Kishimoto T, Taga T (1995) Continuous activation of gp130, a signal-transducing receptor component for interleukin 6-related cytokines, causes myocardial hypertrophy in mice. Proc Natl Acad Sci USA 92:4862–4866Google Scholar
  16. 16.
    Wang Y, Fuller GM (1994) Phosphorylation and internalization of gp130 after IL-6 activation of JAK2 kinase in hepatocytes. Mol Biol Cell 5:819–828Google Scholar
  17. 17.
    Kishimoto T, Taga T, Akira S (1994) Cytokine signal transduction. Cell 76:253–262Google Scholar
  18. 18.
    Lorell BH (1995) Cardiac renin-angiotensin system: role in development of pressure-overload hypertrophy. Can J Cardiol 11(Suppl F):7–12Google Scholar
  19. 19.
    Iwai N, Shimoike H, Kinoshita M, Schelling P, Fischer H, Ganten D (1995) Angiotensin and cell growth: cardiac renin-angiotensin system in the hypertrophied heart. Circulation 92:2690–2696Google Scholar
  20. 20.
    Harada K, Komuro I, Zou Y, Kudoh S, Kijima K, Matsubara H, Sugaya T, Murakami K, Yazaki Y (1998) Acute pressure overload could induce hypertrophic responses in the heart of angiotensin II type Ia knockout mice. Circ Res 82:779–785Google Scholar
  21. 21.
    Harada K, Komuro I, Shiojima I, Hayashi D, Kudoh S, Mizuno T, Kijima K, Matsubara H, Sugaya T, Murakami K, Yazaki Y (1998) Pressure overload induces cardiac hypertrophy in angiotensin II type IA receptor knockout mice. Circulation 97:1952–1959Google Scholar
  22. 22.
    Yamauchi-Takihara K, Ihara Y, Ogata A, Yoshizaki K, Azuma J, Kishimoto T (1995) Hypoxic stress induces cardiac myocyte-derived interleukin-6. Circulation 91:1520–1524Google Scholar
  23. 23.
    Kukielka GL, Smith CW, Manning AM, Youker KA, Michael LH, Entman ML (1995) Induction of interleukin-6 synthesis in the myocardium. Potential role in postreperfusion inflammatory injury. Circulation 92:1866–1875Google Scholar
  24. 24.
    Pennica D, King KL, Shaw KJ, Luis E, Rullamas J, Luoh SM, Darbonne WC, Knutzon DS, Yen R, Chien KR, Baker JB, Wood W (1995) Expression cloning of cardiotrophin 1, a cytokine that induces cardiac myocyte hypertrophy. Proc Natl Acad Sci USA 92:1142–1146Google Scholar
  25. 25.
    Wollert KC, Taga T, Saito M, Narazaki M, Kishimoto T, Glembotski CC, Vernallis AB, Heath JK, Pennica D, Wood WI, Chien KR (1996) Cardiotrophin-1 activates a distinct form of cardiac muscle cell hypertrophy. J Biol Chem 271:9535–9545Google Scholar
  26. 26.
    Pennica D, Wood WI, Chien KR (1996) Cardiotrophin-1: a multifunctional cytokine that signals via LIF receptor-gp 130 dependent pathways. Cytokine Growth Factor Rev 7:81–91Google Scholar
  27. 27.
    Hilton DJ, Nicola NA, Metcalf D (1992) Distribution and binding properties of receptors for leukaemia inhibitory factor. Ciba Found Symp 167:227–239Google Scholar
  28. 28.
    Matsui H, Fujio Y, Kunisada K, Hirota H, Yamauchi-Takihara K (1996) Leukemia inhibitory factor induces a hypertrophic response mediated by gp130 in murine cardiac myocytes. Res Commun Mol Pathol Pharmacol 93:149–162Google Scholar
  29. 29.
    Hibi M, Murakami M, Saito M, Hirano T, Taga T, Kishimoto T (1990) Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell 63:1149–1157Google Scholar
  30. 30.
    Saito M, Yoshida K, Hibi M, Taga T, Kishimoto T (1992) Molecular cloning of a murine IL-6 receptor-associated signal transducer, gp130, and its regulated expression in vivo. J Immunol 148:4066–4071Google Scholar
  31. 31.
    Suematsu S, Matsuda T, Aozasa K, Akira S, Nakano N, Ohno S, Miyazaki J, Yamamura K, Hirano T, Kishimoto T (1989) IgG1 plasmacytosis in interleukin 6 transgenic mice. Proc Natl Acad Sci USA 86:7547–7551Google Scholar
  32. 32.
    Davis S, Aldrich TH, Valenzuela DM, Wong VV, Furth ME, Squinto SP, Yancopoulos GD (1991) The receptor for ciliary neurotrophic factor. Science 253:59–63Google Scholar

Copyright information

© Springer-Verlag 1998

Authors and Affiliations

  • Jing Pan
    • 1
  • Keiichi Fukuda
    • 1
  • Hiroaki Kodama
    • 1
  • Motoaki Sano
    • 1
  • Toshiyuki Takahashi
    • 1
  • Shinji Makino
    • 1
  • Takahiro Kato
    • 1
  • Tomohiro Manabe
    • 1
  • Shingo Hori
    • 2
  • Satoshi Ogawa
    • 1
  1. 1.Cardiopulmonary Division, Department of Internal MedicineKeio UniversityTokyoJapan
  2. 2.Department of Emergency MedicineKeio UniversityTokyoJapan

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