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Angiotensin II-Mediated Stat Signal Transduction: Studies in Neonatal Rat Cardiac Fibroblasts and CHO-K1 Cells Expressing AT1A Receptors

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Angiotensin II Receptor Blockade Physiological and Clinical Implications

Part of the book series: Progress in Experimental Cardiology ((PREC,volume 2))

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Summary

The Signal Transducers and Activators of Transcription (STAT) proteins are a novel class of transcription factors activated by cytokines (Interleukin-6, IL-6) and growth factors (platelet-derived growth factor, PDGF). In cultured neonatal rat cardiac fibroblasts and in CHO-K1 cells expressing angiotensin (Ang) II type 1 receptors (AT1A), called T3CHO/AT1A calls, Ang II stimulated predominandy the tyrosine phosphorylation of STAT3. In these cells, Ang II also tyrosine-phosphorylated STAT1, but tyrosine phosphorylation of STAT1 was significantly lower compared with that of STAT3. Angiotensin II-mediated activation of STAT3 compared with the rapid activation by the cytokine IL-6 was delayed (maximal 2h). However, like cytokines, Ang II rapidly induced serine phosphorylation of STAT3. Using T3CHO/AT1A cells, we examined the potential reasons for the delayed tyrosine phosphorylation of STAT3 by Ang II. We tested the possibility that the delayed tyrosine phosphorylation of STAT3 was due to the induction of an inhibitory pathway, prior to stimulation. A short pretreatment of cells with Ang II transiently inhibited the rapid STAT3 tyrosine phosphorylation by IL-6, and this inhibition could be blocked by pre-exposing the cells with the AT1 antagonist EXP3174. PD98059, a specific inhibitor of MAPK kinase 1, attenuated the inhibitory effects of Ang II. These results suggest that the inhibition by Ang II is a MAPK kinase 1-dependent process. The ability of Ang II to cross-talk with IL-6 signaling suggests a modulatory role for Ang II in cytokine-induced cellular responses.

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References

  1. Raizada MK, Phillips MI, Summers C, eds. 1993. Cellular and molecular biology of renin-angiotensin system. Boca Raton: CRC Press.

    Google Scholar 

  2. Lindpaintner K, Ganten D, eds. 1994. The cardiac renin angiotensin system. Armonk, New York: Fatura Publishing Co.

    Google Scholar 

  3. Booz GW, Baker KM. 1996. The role of renin-angiotensin system in the pathophysiology of cardiac remodeling. Blood Pressure 5(Suppl 2): 10–18.

    Google Scholar 

  4. Schorb W, Booz GW, Dostal DE, Conrad KM, Chang KC, Baker KM. 1993. Angiotensin II is mitogenic in neonatal rat cardiac fibroblasts. Circ Res 72:1245–1254.

    Article  PubMed  CAS  Google Scholar 

  5. Aceto JF, Baker KM. 1990. [Sar1]angiotensin II receptor mediated stimulation of protein synthesis in chick heart cells. Am J Physiol 258:H806–H813.

    PubMed  CAS  Google Scholar 

  6. Berk BC, Vekshtein V, Gordon HM, Tsuda T. 1989. Angiotensin II-stimulated protein synthesis in cultured vascular smooth muscle cells. Hypertension 13:305–314.

    Article  PubMed  CAS  Google Scholar 

  7. Weber H, Taylor DS, Molloy CJ. 1994. Angiotensin II induces delayed mitogenesis and cellular proliferation in rat aortic smooth muscle cells. J Clin Invest 93:788–798.

    Article  PubMed  CAS  Google Scholar 

  8. Timmermans PBMWM, Wong PC, Chiu AT, Herblin WF, Benfield P, Carini DJ, Lee RJ, Wexler RR, Saye JAM, Smith RD. 1993. Angiotensin II receptors and angiotensin II receptor anatagonists. Pharm Rev 45:205–251.

    PubMed  CAS  Google Scholar 

  9. Murphy TJ, Alexander RW, Griendling KK, Runge MS, Bernstein KE. 1991. Isolation of a cDNA encoding the vascular type 1 angiotensin II receptor. Nature 351:233–236.

    Article  PubMed  CAS  Google Scholar 

  10. Sasaki K, Yamano Y, Bardhan S, Iwai N, Murray JJ, Hasegawa M, Matsuda Y, Inagami T. Cloning and expression of a complementary DNA encoding a bovine adrenal angiotensin II type-1 receptor. 1991. Nature 351:230–232.

    Article  PubMed  CAS  Google Scholar 

  11. Kambayashi Y, Bardhan S, Takahashi K, Tsuzuki S, Inui H, Hamakubo T, Inagami T. 1993. Molecular cloning of a novel angiotensin II receptor isoform involved in phosphotyrosine phos-phatase inhibition. J Biol Chem 268:24543–24546.

    PubMed  CAS  Google Scholar 

  12. Mukoyama M, Nakajima M, Horiuchi M, Sasamura H, Pratt RE, Dzau VJ. 1993. Expression cloning of type 2 angiotensin II receptor reveals a unique class of seven transmembrane receptors. J Biol Chem 268:24539–24542.

    PubMed  CAS  Google Scholar 

  13. Molloy CJ, Taylor DS, Weber H. 1993. Angiotensin II stimulation of rapid protein tyrosine phosphorylation and protein kinase activation in rat aortic smooth muscle cells. J Biol Chem 268:7338–7345.

    PubMed  CAS  Google Scholar 

  14. Sadoshima J, Izumo S. 1993. Signal transduction pathways of angiotensin H-induced c-fos gene expression in cardiac myocytes in vitro. Roles of phospholipid-derived second messengers. Circ Res 73:424–438.

    Article  PubMed  CAS  Google Scholar 

  15. Marrero MB, Paxton WG, DuffJL, Berk BC, Bernstein KE. 1994. Angiotensin II stimulates tyrosine phosphorylation of phospholipase C-gamma 1 in vascular smooth muscle cells. J Biol Chem 269:10935–10939.

    PubMed  CAS  Google Scholar 

  16. Booz GW, Dostal DE, Singer HA, Baker KM. 1994. Involvement of protein kinase C and Ca2+ in angiotensin II-induced mitogenisis of cardiac fibroblasts. Am J Physiol 267:C1308–C1318.

    PubMed  CAS  Google Scholar 

  17. Schorb W, Conrad KM, Singer HA, Dostal DE, Baker KM. 1995. Angiotensin II is a potent stimulator of MAP-kinase activity in neonatal rat cardiac fibroblasts. J Mol Cell Cardiol 27:1151–1160.

    Article  PubMed  CAS  Google Scholar 

  18. Zohn IE, Yu H, Li X, Cox AD, Earp HS. 1995. Angiotensin II stimulates calcium-dependent activation of c-Jun N-terminal kinase. Mol Cell Biol 15:6160–6168.

    PubMed  CAS  Google Scholar 

  19. Bhat GJ, Thekkumkara TJ, Thomas WG, Conrad KM, Baker KM. 1994. Angiotensin II stimulates sis-inducing factor like DNA binding activity: Evidence that the AT1A receptor activates transcription factor Stat91 and/or a related protein. J Biol Chem 269:31443–31449.

    PubMed  CAS  Google Scholar 

  20. Bhat GJ, Thekkumkara TJ, Thomas WG, Conrad KM, Baker KM. 1995. Activation of STAT pathway by angiotensin II in T3CHO/AT1A cells: Cross-talk between angiotensin II and interleukin-6 nuclear signaling. J Biol Chem 270:31443–31449.

    Google Scholar 

  21. Bhat GJ, Abraham ST, Baker KM. 1996. Angiotensin II interferes with interleukin-6-induced Stat3 signaling by a pathway involving mitogen-activated protein kinase kinase 1. J Biol Chem 271:22447–22452.

    Article  PubMed  CAS  Google Scholar 

  22. Marrero MB, Schieffer B, Paxton WG, Heerdt L, Berk BC, Delafontaine P, Bernstein KE. 1995. Direct stimulation of JAK-STAT pathway by angiotensin II AT1 receptor. Nature 375:247–250.

    Article  PubMed  CAS  Google Scholar 

  23. Schindler C, Darnell JE Jr. 1995. Transcriptional responses to polypeptide ligands: The JAK-STAT pathway. Annu Rev Biochem 64:621–651.

    Article  PubMed  CAS  Google Scholar 

  24. Ilhe JN. 1995. Cytokine receptor signaling. Nature 377:591–594.

    Article  Google Scholar 

  25. Lehman DW, Pisharody S, Flickinger TW, Commane MA, Sclessinger J, Kerr IM, Levy DE, Stark GR. 1996. Roles of JAKs in activation of STATs and stimulation of c-fos gene expression by epidermal growth factor. Mol Cell Biol. 16:369–375.

    Google Scholar 

  26. Quelle FW, Thierfelder W, Witthuhn BA, Tang BO, Cohen S, Ihle JN. 1995. Phosphorylation and activation of the DNA binding activity of purified Stat1 by the Janus protein tyrosine kinases and the epidermal growth factor receptor. J Biol Chem 270:20775–20780.

    Article  PubMed  CAS  Google Scholar 

  27. Raz R, Durbin JE, Levy DE. 1994. Acute phase response factor and additional members of the interferon regulated gene factor 3 family integrate diverse signals from cytokines, interferons, and growth factors. J Biol Chem 269:24391–24395.

    PubMed  CAS  Google Scholar 

  28. Akira S, Nishio Y, Inoue M, Wang X-J, Wei S, Matsusaka T, Yoshida K, Sudo T, Naruto M, Kishimoto T. 1994. Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130 mediated signaling pathway. Cell 77:63–71.

    Article  PubMed  CAS  Google Scholar 

  29. Booz GW, Baker KM. 1995. Molecular signaling mechanisms controlling the growth and function of cardiac fibroblasts. Cardiovasc Res 30:537–543.

    PubMed  CAS  Google Scholar 

  30. Alessi DR, Cuenda A, Cohen P, Dudley DT, Saltiel AR. 1995. PD98059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J Biol Chem 270:27489–27494.

    Article  PubMed  CAS  Google Scholar 

  31. Dudley DT, Pang L, Decker SJ, Bridges AJ, Saltiel AR. 1995. A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci 92:7686–7689.

    Article  PubMed  CAS  Google Scholar 

  32. Wen Z, Zhong Z, Darnell JE, Jr. 1995. Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 82:241–250.

    Article  PubMed  CAS  Google Scholar 

  33. David M, Petricon E, III, Benjamin C, Pine R, Weber MJ, Larner AC. 1995. Requirement for MAP kinase (ERK2) activity in interferon-α and interferon-β-stimulated gene expression through STAT proteins. Science 269:1721–1723.

    Article  PubMed  CAS  Google Scholar 

  34. Bhat GJ, Baker KM. 1997. Angiotensin II stimulates rapid serine phosphorylation of transcription factor Stat3. Mol Cell Biochem 170:171–176.

    Article  PubMed  CAS  Google Scholar 

  35. Marshall CJ. 1995. Specificity of receptor tyrosine kinase signaling: Transient versus sustained extracellular signal-regulated kinase activation. Cell 80:179–185.

    Article  PubMed  CAS  Google Scholar 

  36. Traverse S, Gomez N, Paterson H, Marshall C, Cohen P. 1992. Sustained activation of the mitogen-activated protein (MAP) kinase cascade may be required for differentiation of PC12 cells. Biochem J 288:351–355.

    PubMed  CAS  Google Scholar 

  37. Wegenka UM, Bushmann J, Luttican C, Heinrich PC, Horn F. 1993. Acute phase response factor, a nuclear factor binding to acute phase response elements, is rapidly activated by interleukin-6 at the post-translational level. Mol Cell Biol 13:276–288.

    PubMed  CAS  Google Scholar 

  38. Bugno M, Graeve L, Gatsios P, Koj A, Heinrich PC, Travis J, Kordula T. 1995. Identification of the interleukin-6/oncostatin M response element in the rat tissue inhibitor of metalloproteinases-1 (TIMP-1) promoter. Nucl Acids Res 23:5041–5047.

    Article  PubMed  CAS  Google Scholar 

  39. Kordula T, Ripperger J, Morella KK, Travis J, Baumann H. 1996. Two separate signal transducers and activators of transcription proteins regulate transcription of the serine proteinase inhibitor-3 gene in hepatic cells. J Biol Chem 271:6752–6757.

    Article  PubMed  CAS  Google Scholar 

  40. Hou J, Baichwal V, Cao Z. 1994. Regulatory elements and transcription factors controlling basal and cytokine induced expression of the gene encoding intercellular adhesion molecule 1. Proc Natl Acad Sci USA 91:11641–11645.

    Article  PubMed  CAS  Google Scholar 

  41. Taubman MB, Berk BC, Izumo S, Tsuda T, Alexander RW, Nadal-Ginard M. 1989. Angiotensin II induces c-fos mRNA in rat aortic smooth muscle cells. J Biol Chem 264:526–530.

    PubMed  CAS  Google Scholar 

  42. Chua CC, Hamdy RC, Chua BH. 1996. Angiotensin II induces TIMP-1 production in rat heart endothelial cells. Biochem Biophys Acta 1311:175–180.

    Article  PubMed  Google Scholar 

  43. Kordula T, Guttgemann I, Rose-John S, Roeb E, Osthues A, Tschesche H, Koj A, Heinrich PC, Graeve L. 1992. Synthesis of tissue inhibitor of metalloproteinase-1 (TIMP-1) in human hepatoma cells (HepG2). FEBS Lett 313:143–147.

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. University of Texas Health Center, Tyler, TX, USA

    G. Jayarama Bhat

  2. Weis Center for Research, Geisinger Clinic, Danville, PA, USA

    Kenneth M. Baker

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  1. G. Jayarama Bhat
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Editor information

Editors and Affiliations

  1. Institute of Cardiovascular Sciences St. Boniface General Hospital Research Centre Faculty of Medicine, University of Manitoba, Winnipeg, Canada

    Naranjan S. Dhalla Ph.D., M.D. (Hon.) (Distinguished Professor and Director MRC Group in Experimental Cardiology), Peter Zahradka Ph.D. (Associate Professor), Ian M. C. Dixon Ph.D. (Assistant Professor) & Robert E. Beamish M.D. (Professor Emeritus) (Distinguished Professor and Director MRC Group in Experimental Cardiology),  (Associate Professor),  (Assistant Professor) &  (Professor Emeritus)

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Bhat, G.J., Baker, K.M. (1998). Angiotensin II-Mediated Stat Signal Transduction: Studies in Neonatal Rat Cardiac Fibroblasts and CHO-K1 Cells Expressing AT1A Receptors. In: Dhalla, N.S., Zahradka, P., Dixon, I.M.C., Beamish, R.E. (eds) Angiotensin II Receptor Blockade Physiological and Clinical Implications. Progress in Experimental Cardiology, vol 2. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-5743-2_26

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  • DOI: https://doi.org/10.1007/978-1-4615-5743-2_26

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-7631-6

  • Online ISBN: 978-1-4615-5743-2

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