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Molecular aspects of mechanical stress-induced cardiac hypertrophy

  • Part II: Cardiac Hypertrophy and Failure
  • Published:
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Abstract

To elucidate the signal transduction pathway from external stimuli to nuclear gene expression in mechanical stress-induced cardiac hypertrophy, we examined the time course of activation of protein kinases such as Raf-1 kinase (Raf-1), mitogen-activated protein kinase kinase (MAPKK), MAP kinases (MAPKs) and 90-kDa ribosomal S6 kinase (p90rsk) in neonatal rat cardiomyocytes. Mechanical stretch rapidly activated Raf-1 and its maximal activation was observed at 1–2 min after stretch. The activity of MAPKK was also increased by stretch, with a peak at 5 min after stretch. In addition, MAPKs and p90rsk were maximally activated at 8 min and at 10–30 min after stretch, respectively. Next, the relationship between mechanical stress-induced hypertrophy and the cardiac renin-angiotensin system was investigated. When the stretch-conditioned culture medium was transferred to the culture dish of non-stretched cardiac myocytes, the medium activated MAPK activity slightly but significantly, and the activation was completely blocked by the type 1 angiotensin II receptor antagonist, CV-11974. However, activation of Raf-1 and MAPKs provoked by stretching cardiomyocytes was only partially suppressed by pretreatment with CV-11974. These results suggest that mechanical stress activates the protein kinase cascade of phosphorylation in cardiac myocytes in the order of Raf-1, MAPKK, MAPKs and p90rsk, and that angiotensin II, which is secreted from stretched myocytes, activates a part of these protein kinases.

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Abbreviations

MAPK:

mitogen-activated protein kinase

MAPKK:

MAP kinase kinase

Raf-1 - Raf- 1 kinase:

p90rsk, 90 kDa ribosomal S6 kinase; AngII - angiotensin II

MAPKKK:

MAP kinase kinase kinase

rMAPK:

recombinant MAPKK fused to gluthathione S transferase

MMAKK:

recombinant MAPK fused to maltose binding protein

MBP:

myelin basic protein

ACE:

angiotensin-converting enzyme

References

  1. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP: Prognostic implications of echocardiographically determined left ventricular mass in the Framingham heart study. N Eng J Med 322: 1561–1566, 1990

    Google Scholar 

  2. Komuro I, Yazaki Y: Control of cardiac gene expression by mechanical stress. Annu Rev Physiol 55: 55–75, 1993

    Article  PubMed  Google Scholar 

  3. Komuro I, Kurabayashi M, Takaku F, Yazaki Y: Expression of cellular oncogenes in the myocardium during the developmental stage and pressure overload hypertrophy of the rat heart. Cite Res 62: 1075–1079, 1988

    Google Scholar 

  4. Mulvagh SL, Michael LH, Perryman MB, Roberts R, Sehneider MD: A hemodynamic load in vivo induces cardiac expression of the cellular oncogene, c-myc. Biochem Biophys Res Commun 147: 627–636.

  5. Komuro I, Kaida T, Shibazaki Y, Kurabayashi M, Takaku Yazaki Y: Stretching cardiac myocytes stimulates proto-oncogene expression. J Biol Chem 265: 3595–3598, 1990

    PubMed  Google Scholar 

  6. Komuro I, Katoh Y, Kaida T, Shibazaki Y, Kurabayashi M, Takaku F, Yazaki Y. Mechanical loading stimulates cell hypertrophy and specific gene expression in cultured rat cardiac myocytes. J Biol Chem 266:1265–1268,1991

    PubMed  Google Scholar 

  7. Yamazaki T, Tobe K, Hoh E, Maemura K, Kaida T, Komuro I, Tamemoto H, Kadowaki T, Nagai R, Yazaki Y: Mechanical loading activates mitogen-activated protein kinase and S6 peptide kinase in cultured rat cardiac myocytes. J Biol Chem 268: 12069–12076, 1993

    PubMed  Google Scholar 

  8. Gomez N, Cohen P: Dissection of the protein kinase cascade by which nerve growth factor activates MAP kinases. Nature 353: 170–173, 1991

    Article  PubMed  Google Scholar 

  9. Ahn NG, Seger R, Bratlien RL, Diltz CD, Tonks NK, Krebs EG: Multiple components in an EGF-stimulated protein kinase cascade. In vitro activation of a MBP/MAP2 kinase. J Biol Chem 266: 4220–4225, 1991

    PubMed  Google Scholar 

  10. Matsuda S, Kosako H, Takenaka K, Moriyama K, Sakai H, Akiyama T, Gotoh Y, Nishida E: Xenopus MAP kinase activator: identification and function as a key intermediate in the phosphorylation cascade. EMBO J 11: 973–829, 1992

    PubMed  Google Scholar 

  11. Zheng C-F, Guan K-L: Activation of MEK family kinase requires phosphorylation of two conserved Ser/Thr residues. EMBO J 13: 1123–1131, 1994

    PubMed  Google Scholar 

  12. Kyriakis JM, App H, Zhang X, Banerjee P, Brautigan DL, Rapp UR, Avruch J: Raf-1 activates MAP kinase-kinase. Nature 358: 417–421, 1992

    Article  PubMed  Google Scholar 

  13. Davis RJ: The mitogen-activated protein kinase signal transduction pathway. J Biol Chem 268: 14553–14556, 1993

    Google Scholar 

  14. Sturgill TW, Ray LB, Erickson E, Maller JL: Insulin-stimulated MAP2 kinase phosphorylates and activates ribosomal protein S6 kinase II Nature 334: 715–718, 1988

    Article  PubMed  Google Scholar 

  15. Ward GE, Kirschner MW: Identification of cell cycle-regulated phosphorylation sites on nuclear lamin C. Cell 61: 561–577, 1990

    PubMed  Google Scholar 

  16. Lindpaintner K, Ganten D: The cardiac renin-angiotensin system: an appraisal of present experimental and clinical evidence. Circ Res 68: 905–921, 1991

    PubMed  Google Scholar 

  17. Baker KM, Booz GW, Dostal DE: Cardiac actions of angiotensin II: role of an intracardiac renin-angiotensin system. Annu Rev Physiol 54: 227–241, 1992

    Article  PubMed  Google Scholar 

  18. Simpson P, Savion S: Differentiation of rat myocytes in single cell cultures with and without proliferating nonmyocardial cells. Circ Res 50: 101–116, 1982

    PubMed  Google Scholar 

  19. Lange-Carter CA, Pleiman AM, Blumer KJ, Johnson GL: A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf. Science 260: 315–319, 1993

    PubMed  Google Scholar 

  20. Izumi T, Tamemoto H, Nagao M, Kadowaki T, Takaku F, Kasuga M: Insulin and platelet derived growth factor stimulate phosphorylation of the c-raf product at serine and threonine residues in intact cells. J Biol Chem 266: 7933–7939, 1991

    PubMed  Google Scholar 

  21. Ueki K, Matsuda S, Tobe K, Gotoh Y, Tamemoto H, Yachi M, Akanuma Y, Yazaki Y, Nishida E, Kadowaki T: Feedback regulation of mitogenactivated protein kinase kinase kinase activity of c-Raf-1by insulin and phorbol ester stimulation. J Biol Chem 269: 15756–15761, 1994

    PubMed  Google Scholar 

  22. Kosako H, Nishida E, Gotoh Y: cDNA cloning of MAP kinase; kinase reveals kinase cascade pathways in yeasts to vertebrates. EMBO J 12: 787–794, 1993

    PubMed  Google Scholar 

  23. Tobe K, Kadowaki T, Tamemoto H. Ueki K, Hara K, Koshio O, Momomura K, Gotoh Y, Nishida E, Akanuma Y, Yazaki Y, Kasuga M: Insulin and 12-O-tetradecanoylphorbol-13-acetate activation of two immunologically distinct myelin basic protein/microtubule-associated protein 2 (MBP/MAP2) kinases via de novo phosphorylation of threonine and tyrosine residues. J Biol Chem 266: 24793–24803, 1991

    PubMed  Google Scholar 

  24. Tobe K, Kadowaki T, Hara K, Gotoh Y, Kosako H, Matsuda S, Tamemoto H, Ucki K, Akanuma Y, Nishida E, Yazaki Y: Sequential activation of MAP kinase activator, MAP kinases, and S6 peptide kinase in intact rat liver following insulin injection. J Biol Chem 267: 21089–21097, 1992

    PubMed  Google Scholar 

  25. Sadoshima J, Xu Y, Slayter HS, Izumo S: Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell 75: 977–984, 1993

    Article  PubMed  Google Scholar 

  26. Kojima M, Shiojima I, Yamazaki T, Komuro I, Zou Y, Wang Y, Mizuno T, Ueki K, Tobe K, Kadowaki T, Nagai R, Yazaki Y: Angiotensin II receptor antagonist TCV-116 induces regression of hypertensive left ventricular hypertrophy in vivo and inhibits intracellular signaling pathway of stretch-mediated cardiomyocyte hypertrophy in vitro. Circulation 89: 2204–2211, 1994

    PubMed  Google Scholar 

  27. Komuro I, Shibazaki Y Kurabavashi M, Takaku F. Yazaki Y: Molecular cloning of gene sequences from rat heart rapidly responsive to pressure overload. Circ Res 966: 979–985, 1990

    Google Scholar 

  28. Schunkert H, Dzau VJ, Tang SS, Hirsch AT, Apstein CS, Lorell BH: Increased rat cardiac angiotensin converting enzyme activity and mRNA expression in pressure overload left ventricular hypertrophy: effect on coronary resistance, contractility, and relaxation. J Clin Invest 86: 1913–1920, 1990

    PubMed  Google Scholar 

  29. Linz W, Schoelkens BA, Ganten D: Converting enzyme inhibitor specifically prevents development and induces the regression of cardiac hypertrophy in rats. Clin Exp Hypertens 11: 1325–1350, 1989

    Google Scholar 

  30. Baker KM, Cherin MI, Wixon SK, Aceto JF: Renin-angiotensin system involvement in pressure-overload cardiac hypertrophy in rats. Am J Physiol 259: H324-H332, 1990

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113, Tokyo, Japan

    Tsutomu Yamazaki, Issei Komuro & Yoshio Yazaki

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  1. Tsutomu Yamazaki
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  2. Issei Komuro
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  3. Yoshio Yazaki
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Yamazaki, T., Komuro, I. & Yazaki, Y. Molecular aspects of mechanical stress-induced cardiac hypertrophy. Mol Cell Biochem 163, 197–201 (1996). https://doi.org/10.1007/BF00408658

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