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Integrin-Dependent and -Independent Signaling During Pressure-Overload Cardiac Hypertrophy

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Book cover The Hypertrophied Heart

Part of the book series: Progress in Experimental Cardiology ((PREC,volume 3))

Summary

In an attempt to uncover the linkage between hemodynamic load and cardiac hypertrophy, we focused on the cytoskeletal (CSK) assembly of signaling proteins in pressure-overloaded feline myocardium. Analysis showed CSK association of c-Src, β3-integrin, FAK, PTP-1B, and p130Cas in 4 to 48 hour pressure overloaded (PO) myocardium. This assembly was accompanied by increased amounts of both total fibronectin (FN) and vitronectin (VN) and their attachment to the cardiocyte sarcolemma, indicating that a change in extracellular matrix (ECM) composition might be responsible for the CSK assembly of these signaling proteins. Furthermore, analysis with adult feline cardiocytes cultured in a three-dimensional (3-D) gel matrix made of either collagen containing FN and VN or of agarose alone for 12 hours revealed a CSK assembly of some of the signaling proteins only in collagen matrix, an event that could be blocked with RGD peptide. To investigate the role of CSK-assembled signaling proteins, activation of the two S6 kinase (S6K) isoforms, p70S6K and p85S6K, that are involved in translational and transcriptional activation was measured in PO myocardium. While both isoforms are activated substantially, p70S6K activation occurred maximally at 1 hour of pressure overload prior to the CSK assembly of signaling proteins. The activation of both isoforms of S6K was found to be mediated by a PI 3-kinase-independent pathway with the possible involvement of protein kinase C. Furthermore, studies performed in vitro by embedding adult cardiocytes either in collagen or in agarose gels and stimulating them electrically to contract showed S6K activation in both types of gels, although CSK association of signaling proteins was present only in the collagen gel matrix. Therefore, these studies demonstrate that pressure overload activates both integrin-dependent and -independent signaling, which results, respectively, in cytoskeletal recruitment of signaling proteins and in S6K activation. Both may play critical roles in hypertrophic growth regulation.

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References

  1. Cooper G. 1987. Cardiocyte adaptation to chronically altered load. Annu Rev Physiol 49:501–518.

    Article  PubMed  CAS  Google Scholar 

  2. Chien KR, Zhu H, Knowlton KU, Miller-Hance W, van-Bilsen M, O’Brien TX, Evans SM. 1993. Transcriptional regulation during cardiac growth and development. Annu Rev Physiol 55:77–95.

    Article  PubMed  CAS  Google Scholar 

  3. Miyamoto S, Teramoto H, Coso OA, Gutkind JS, Burbelo PD, Akiyama SK, Yamada KM. 1995. Integrin function: molecular hierarchies of cytoskeletal and signaling molecules. J Cell Biol 131:791–805.

    Article  PubMed  CAS  Google Scholar 

  4. Haimovich B, Lipfert L, Brugge JS, Shattil SJ. 1993. Tyrosine phosphorylation and cytoskeletal reorganization in platelets are triggered by interaction of integrin receptors with their immobilized ligands.J Biol Chem 268:15868–15877.

    PubMed  CAS  Google Scholar 

  5. Chen WT, Singer SJ. 1982. Immunoelectron microscopic studies of the sites of cell-substratum and cell-cell contacts in cultured fibroblasts. J Cell Biol 95:205–222.

    Article  PubMed  CAS  Google Scholar 

  6. Burridge K, Fath K, Kelly T, Nuckolls G, Turner C. Focal adhesions: transmembrane junctions between the extracellular matrix and the cytoskeleton. Annu Rev Cell Biol 4:487–525.

    Google Scholar 

  7. Turner CE„ Burridge K. 1991. Transmembrane molecular assemblies in cell-extracellular matrix interactions. Curr Opin Cell Biol 3:849–853.

    Article  PubMed  Google Scholar 

  8. Schaller MD, Parsons JT. 1994. Focal adhesion kinase and associated proteins. Curr Opin Cell Biol 6:705–710.

    Article  PubMed  CAS  Google Scholar 

  9. Shattil SJ, Haimovich B, Cunningham M, Lipfert L, Parsons JT, Ginsberg MH, Brugge JS. 1994. Tyrosine phosphorylation of pp125FAK in platelets requires coordinated signaling through integrin and agonist receptors. J Biol Chem 269:14738–14745.

    PubMed  CAS  Google Scholar 

  10. Hynes RO. 1992. Integrins: versatility, modulation, and signaling in cell adhesion. Cell 69:11–25.

    Article  PubMed  CAS  Google Scholar 

  11. Hughes PE, Pfaff M. 1998. Integrin affinity modulation. Trends cell Biol 8:359–364.

    Article  PubMed  CAS  Google Scholar 

  12. Collo G, Starr L, Quaranta V. 1993. A new isoform of the laminin receptor integrin alpha 7 beta 1 is developmentally regulated in skeletal muscle. J Biol Chem 268:19019–19024.

    PubMed  CAS  Google Scholar 

  13. Ashizawa N, Graf K, Do YS, Nunohiro T, Giachelli CM, Meehan WP, Tuan TL, Hsueh WA. 1996. Osteopontin is produced by rat cardiac fibroblasts and mediates A(II)-induced DNA synthesis and collagen gel contraction. J Clin Invest 98:2218–2227.

    Article  PubMed  CAS  Google Scholar 

  14. Kuppuswamy D, Kerr C, Narishige T, Kasi VS, Menick DR, Cooper G. 1997. Association of tyrosine-phosphorylated c-Src with the cytoskeleton of hypertrophying myocardium. J Biol Chem 272:4500–4508.

    Article  PubMed  CAS  Google Scholar 

  15. Terrario L, Rubin K, Gullberg D, Balog E, Carver W, Jyring R, Borg TK. 1991. Expression of collagen-binding integrins during cardiac development and hypertrophy. Circ Res 68:734–744.

    Article  Google Scholar 

  16. Samuel JL, Barrieux A, Dufour S, Dubus I, Contard F, Koteliansky V, Farhadian F, Marotte F, Thiery JP, Rappaport L. 1991. Accumulation of fetal fibronectin mRNAs during the development of rat cardiac hypertrophy induced by pressure overload. J Clin Invest 88:1737–1746.

    Article  PubMed  CAS  Google Scholar 

  17. Villarreal FJ, Dillmann WH. 1992. Cardiac hypertrophy-induced changes in mRNA levels for TGF-beta 1, fibronectin, and collagen, Am J Physiol 262(6, Pt 2):H1861–H1866.

    PubMed  CAS  Google Scholar 

  18. Clark EA, Brugge JS. 1995. Integrins and signal transduction pathways: the rod taken. Science 268:233–239.

    Article  PubMed  CAS  Google Scholar 

  19. Schlaepfer DD, Hunter T. 1998. Integrin signalling and tyrosine phosphorylation: just the FAKs? Trends Cell Biol 8:151–157.

    Article  PubMed  CAS  Google Scholar 

  20. Ross RS, Pham C, Shai SY, Goldhaber JI, Fenczik C, Glembotski CC, Ginsberg MH, Loftus JC. 1998. Betal integrins participate in the hypertrophic response of rat ventricular myocytes. Circ Res 82:1160–1172.

    Article  PubMed  CAS  Google Scholar 

  21. Schaller MD, Hildebrand JD, Shannon JD, Fox JW, Vines RR, Parsons JT. 1994. Autophosphorylation of the focal adhesion kinase, pp125FAK, directs SH2-dependent binding of pp60src. Mol Cell Biol 14:1680–1688.

    PubMed  CAS  Google Scholar 

  22. Horwitz A, Duggan K, Buck C, Beckerle MC, Burridge K. 1986. Interaction of plasma membrane fibronectin receptor with talin: a transmembrane linkage. Nature 320:531–533.

    Article  PubMed  CAS  Google Scholar 

  23. Juliano RL, Haskill S. 1993. Signal transduction from the extracellular matrix. J Cell Biol 120:577–585.

    Article  PubMed  CAS  Google Scholar 

  24. Ingber DE. 1993. Cellular tensegrity: defining new rules of biological design that govern the cytoskeleton. J Cell Sci 104(Pt 3):613–627.

    PubMed  Google Scholar 

  25. Schlaepfer DD, Hanks SK, Hunter T, van der Geer P. 1994. Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase. Nature 372:786–791.

    PubMed  CAS  Google Scholar 

  26. Fox JE, Lipfert L, Clark EA, Reynolds CC, Austin CD, Brugge JS. 1993. On the role of the platelet membrane skeleton in mediating signal transduction. Association of GP IIb–IIIa, pp60c-src, pp62c-yes, and the p21ras GTPase-activating protein with the membrane skeleton. J Biol Chem 268:25973–25984.

    PubMed  CAS  Google Scholar 

  27. Weernink PA, Rijksen G. 1995. Activation and translocation of c-Src to the cytoskeleton by both platelet-derived growth factor and epidermal growth factor. J Biol Chem 270:2264–2267.

    Article  PubMed  CAS  Google Scholar 

  28. Shyy JY, Chien S. 1997. Role of integrins in cellular responses to mechanical stress and adhesion. Curr Opin Cell Biol 9:707–713.

    Article  PubMed  CAS  Google Scholar 

  29. Rabkin SW, Damen JE, Goutsouliak V, Krystal G. 1996. Cardiac hypertrophy in the Dahl rat is associated with increased tyrosine phosphorylation of several cytosolic proteins, including a 120 kDa protein. Am J Hypertens 9:230–236.

    Article  PubMed  CAS  Google Scholar 

  30. Melillo G, Lima JA, Judd RM, Goldschmidt-Clermont PJ, Silverman HS. 1996. Intrinsic myocyte dysfunction and tyrosine kinase pathway activation underlie the impaired wall thickening of adjacent regions during postinfarct left ventricular remodeling. Circulation 93:1447–1458.

    Article  PubMed  CAS  Google Scholar 

  31. Kudoh S, Komuro I, Hiroi Y, Zou Y, Harada K, Sugava T, Takekoshi N, Murakami K, Kadowaki T, Yazaki Y. 1998. Mechanical stretch induces hypertrophic responses in cardiac myocytes of angiotensin II type 1a receptor knockout mice. J Biol Chem 273:24037–24043.

    Article  PubMed  CAS  Google Scholar 

  32. Ben-Ze’ev A, Robinson GS, Bucher NL, Farmer SR. 1988. Cell-cell and cell-matrix interactions differentially regulate the expression of hepatic and cytoskeletal genes in primary cultures of rat hepatocytes. Proc Natl Acad Sci USA 85:2161–2165.

    Article  PubMed  Google Scholar 

  33. Pawson T, Scott JD. 1997. Signaling through scaffold, anchoring, and adaptor proteins. Science 278:2075–2080.

    Article  PubMed  CAS  Google Scholar 

  34. Graf K, Do YS, Ashizawa N, Meehan WP, Giachelli CM, Marboe CC, Fleck E, Hsueh WA. 1997. Myocardial osteopontin expression is associated with left ventricular hypertrophy. Circulation 96: 3063–3071.

    Article  PubMed  CAS  Google Scholar 

  35. Boluyt MO, Bing OH. 1995. The lonely failing heart: a case for ECM genes. Cardiovasc Res 30: 836–840.

    PubMed  CAS  Google Scholar 

  36. Howe A, Aplin AE, Alahari SK, Juliano RL. 1998. Integrin signaling and cell growth control. Curr Opin Cell Biol 10:220–231.

    CAS  Google Scholar 

  37. Schlaepfer DD, Jones KC, Hunter T. 1998. Multiple Grb2-mediated integrin-stimulated signaling pathways to ERK2/mitogen-activated protein kinase: summation of both c-Src- and focal adhesion kinase-initiated tyrosine phosphorylation events. Mol Cell Biol 18:2571–2585.

    PubMed  CAS  Google Scholar 

  38. Lin TH, Aplin AE, Shen Y, Chen Q, Schaller M, Romer L, Aukhil I, Juliano RL. 1997. Integrin-mediated activation of MAP kinase is independent of FAK: evidence for dual integrin signaling pathways in fibroblasts. J Cell Biol 136:1385–1395.

    Article  PubMed  CAS  Google Scholar 

  39. Van Aelst L, D’Souza-Schorey C. 1997. Rho GTPases and signaling networks. Genes Dev 11:2295–2322.

    Article  PubMed  Google Scholar 

  40. Scatena M, Almeida M, Chaisson ML, Fausto N, Nicosia RF, Giachelli CM. 1998. NF-kappaB mediates alphavbeta3 integrin-induced endothelial cell survival. J Cell Biol 141:1083–1093.

    Article  PubMed  CAS  Google Scholar 

  41. Malik RK, Parsons JT. 1996. Integrin-dependent activation of the p70 ribosomal S6 kinase signaling pathway. J Biol Chem 271:29785–29791.

    Article  PubMed  CAS  Google Scholar 

  42. Khwaja A, Rodriguez-Viciana P, Wennstrom S, Warne PH, Downward J. 1997. Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. EMBO J 16:2783–2793.

    Article  PubMed  CAS  Google Scholar 

  43. Jefferies HB, Reinhard C, Kozma SC, Thomas G. 1994. Rapamycin selectively represses translation of the “polypyrimidine tract” mRNA family. Proc Nad Acad Sci USA 91:4441–4445.

    Article  CAS  Google Scholar 

  44. Laser M, Kasi VS, Hamawaki M, Cooper G 4th, Kerr CM, Kuppuswamy D. 1998. Differential activation of p70 and p85 S6 kinase isoforms during cardiac hypertrophy in the adult mammal. J Biol Chem 273:24610–24619.

    Article  PubMed  CAS  Google Scholar 

  45. Ferrari S, Pearson RB, Siegmann M, Kozma SC, Thomas G. 1993. The immunosuppressant rapamycin induces inactivation of p70s6k through dephosphorylation of a novel set of sites. J Biol Chem 268:16091–16094.

    PubMed  CAS  Google Scholar 

  46. Homma T, Akai Y, Burns KD, Harris RC. 1992. Activation of S6 kinase by repeated cycles of stretching and relaxation in rat glomerular mesangial cells. Evidence for involvement of protein kinase C. J Biol Chem 267:23129–23135.

    PubMed  CAS  Google Scholar 

  47. Monfar M, Lemon KP, Grammer TC, Cheatham L, Chung J, Vlahos CJ, Blenis J. 1995. Activation of pp70/85 S6 kinases in interleukin-2-responsive lymphoid cells is mediated by phosphatidylinositol 3-kinase and inhibited by cyclic AMP. Mol Cell Biol 15:326–337.

    PubMed  CAS  Google Scholar 

  48. Morrison DK. 1995. Mechanisms regulating Raf-1 activity in signal transduction pathways. Mol Reprod Dev 42:507–514.

    Article  PubMed  CAS  Google Scholar 

  49. Lenormand P, McMahon M, Pouyssegur J. 1996. Oncogenic Raf-1 activates p70 S6 kinase via a mitogen-activated protein kinase-independent pathway. J Biol Chem 271:15762–15768.

    Article  PubMed  CAS  Google Scholar 

  50. Stokoe D, McCormick F. 1997. Activation of c-Raf-1 by Ras and Src through different mechanisms: activation in vivo and in vitro. EMBO J 16:2384–2396.

    Article  PubMed  CAS  Google Scholar 

  51. de Groot RP, Ballou LM, Sassone-Corsi P. 1994. Positive regulation of the cAMP-responsive activator CREM by the p70 S6 kinase: an alternative route to mitogen-induced gene expression. Cell 79:81–91.

    Article  PubMed  Google Scholar 

  52. Rozich JD, Barnes MA, Schmid PG, Zile MR, McDermott PJ, Cooper G. 1995. Load effects on gene expression during cardiac hypertrophy. J Mol Cell Cardiol 27:485–499.

    Article  PubMed  CAS  Google Scholar 

  53. Nahman NS Jr, Rothe KL, Falkenhain ME, Frazer KM, Dacio LE, Madia JD, Leonhart KL, Kronenberger JC, Stauch DA. 1996. Angiotensin II induction of fibronectin biosynthesis in cultured human mesangial cells: association with CREB transcription factor activation. J Lab Clin Med 127:599–611.

    Article  PubMed  CAS  Google Scholar 

  54. Eschenhagen T, Fink C, Remmers U, Scholz H, Wattchow J, Weil J, Zimmermann W, Dohmen HH, Schafter H, Bishopric N, Wakatsuki T, Elson EL. 1997. Three-dimensional reconstitution of embryonic cardiomyocytes in a collagen matrix: a new heart muscle model system. FASEB J 11:683–694.

    PubMed  CAS  Google Scholar 

  55. VanWinkle WB, Snuggs MB, Buja LM. 1996. Cardiogel: a biosynthetic extracellular matrix for cardiomyocyte culture. In Vitro Cell Dev Biol Anim 32:478–485.

    Google Scholar 

  56. Nagai T, Laser M, Baku CF, Zile MR, Cooper G IV, Kuppuswamy D. In press. β3-integrin-mediated focal adhesion complex formation: studies of adult cardiocytes embedded in a three-dimensional collagen matrix. Am J Cardiol.

    Google Scholar 

  57. Belkin AM, Retta SF, Pletjushkina OY, Balzac F, Silengo L, Fassler R, Koteliansky VE, Burridge K, Tarane G. 1997. Muscle beta1D integrin reinforces the cytoskeleton-matrix link: modulation of integrin adhesive function by alternative splicing. J Cell Biol 139:1583–1595.

    Article  PubMed  CAS  Google Scholar 

  58. Pasqualini R, Koivunen E, Ruoslahti E. 1996. Peptides in cell adhesion: powerful tools for the study of integrin-ligand interactions. Braz J Med Biol Res 29:1151–1158.

    PubMed  CAS  Google Scholar 

  59. Daniel JM, Reynolds AB. 1997. Tyrosine phosphorylation and cadherin/catenin function. Bioessays 19:883–891.

    Article  PubMed  CAS  Google Scholar 

  60. Miyamoto S, Teramoto H, Coso OA, Gutkind JS, Burbelo PD, Akiyama SK, Yamada KM. 1995. Integrin function: molecular hierarchies of cytoskeletal and signaling molecules. J Cell Biol 131:791–805.

    Article  PubMed  CAS  Google Scholar 

  61. Ivester CT, Tuxworth WJ, Cooper G IV, McDermott PJ. 1995. Contraction accelerates myosin heavy chain synthesis rates in adult cardiocytes by an increase in the translational initiation. J Biol Chem 270:21950–21957.

    Article  PubMed  CAS  Google Scholar 

  62. Wada H, Zile MR, Ivester G, Cooper G, McDermott PJ. 1996. Comparative effects of contraction and angiotensin II on growth of adult feline cardiocytes in primary culture. Am J Physiol 271: H29–H37.

    PubMed  CAS  Google Scholar 

  63. Kolanus W, Seed B. 1997. Integrins and inside-out signal transduction: converging signals from PKC and PIP3. Curr Opin Cell Biol 9:725–731.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Cardiology Section of the Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, 29425, USA

    Martin Laser, Toshio Nagai, Vijaykumar S. Kasi, Catalin F. Baicu, Christopher D. Willey, Charlene M. Kerr, Michael R. Zile, George Cooper IV & Dhandapani Kuppuswamy

  2. The Departments of Physiology, Medical University of South Carolina, Charleston, South Carolina, 29425, USA

    George Cooper IV

  3. Cell Biology, Gazes Cardiac Research Institute, Medical University of South Carolina, Charleston, South Carolina, 29425, USA

    Dhandapani Kuppuswamy

  4. Veterans Administration Medical Center Charleston, South Carolina, 29401, USA

    Michael R. Zile & George Cooper IV

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  1. Martin Laser
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  2. Toshio Nagai
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  3. Vijaykumar S. Kasi
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Editors and Affiliations

  1. Department of Internal Medicine, Aoto Hospital, Jikei University School of Medicine, Tokyo, Japan

    Nobuakira Takeda M.D., Ph.D. (Associate Professor) (Associate Professor)

  2. Jikei University School of Medicine, Tokyo, Japan

    Makoto Nagano M.D., Ph.D. (Professor Emeritus) (Professor Emeritus)

  3. 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.), D.Sc. (Hon) (Distinguished Professor and Director) (Distinguished Professor and Director)

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Laser, M. et al. (2000). Integrin-Dependent and -Independent Signaling During Pressure-Overload Cardiac Hypertrophy. In: Takeda, N., Nagano, M., Dhalla, N.S. (eds) The Hypertrophied Heart. Progress in Experimental Cardiology, vol 3. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-4423-4_12

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  • DOI: https://doi.org/10.1007/978-1-4615-4423-4_12

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