Skip to main content
SpringerLink
Log in

Angiotensin II signalling pathways in cardiac fibroblasts: Conventional versus novel mechanisms in mediating cardiac growth and function

  • Part I: Basic Mechanisms
  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Angiotensin II has been demonstrated to be involved in the regulation of cellular growth of several tissues in response to developmental, physiological, and pathophysiological processes. Angiotensin 11 has been implicated in the developmental growth of the left ventricle in the neonate and remodeling of the heart following chronic hypertension and myocardial infarction. The inhibition of DNA synthesis and collagen deposition in myocardial interstitium following myocardial infarction by angiotensin converting enzyme inhibitor, suggests that angiotensin II mediates interstitial and perivascular fibrobrosis by preventing fibroblast proliferation. In the past, little attention was focused on the identity and functional roles of cardiac fibroblasts. Recent in vitro studies utilizing cultured cardiac fibroblasts demonstrate that angiotensin II, acting via the AT1 receptor, initiates intracellular signalling pathways in common with those of peptide growth factors. Below, we describe growth-related aspects of cardiac fibroblasts with respect to angiotensin II receptors, conventional and novel signal transduction systems, secretion of extracellular matrix proteins and growth factors, and localization of renin-angiotensin system components.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Dostal DE, Baker KM: An intracardiac renin-angiotensin system in normal and failing hearts. Trends in Cardiovas Med 3: 67–74, 1993

    Google Scholar 

  2. Lindpaintner K, Ganten D: The cardiac renin-angiotensin system: An appraisal of present experimental and clinical evidence. Circ Res 68: 905–928, 1991

    Google Scholar 

  3. Dostal DE, Baker KM: Angiotensin II stimulation of left ventricular hypertrophy in adult rat heart: mediation by the AT1 receptor. Am J Hypertens 5: 276–280, 1992

    Google Scholar 

  4. Beinlich CJ, White GJ, Baker KM, Morgan HE: Angiotensin II and left ventricular growth in newborn pig heart. J Mol Cell Cardiol 23: 1031–1038, 1991

    Google Scholar 

  5. Beinlich CJ, Baker KM, White GJ, Morgan HE: Control of growth in the neonatal pig heart. Am J Physiol 261: 3–7, 1991

    Google Scholar 

  6. Gilbert BW: ACE inhibitor and regression of left ventricular hypertrophy. Clin Cardiol 15: 711–714, 1992

    Google Scholar 

  7. Grove D, Zak R, Nair KG, Aschenbrenner V: Biochemical correlation of cardiac hypertrophy: Observations on the cellular organization of growth during myocardial hypertrophy in the rat. Circ Res 25: 473–485, 1969

    Google Scholar 

  8. Schorb W, Booz GW, Dostal DE, Conrad KM, Chang KC, Baker KM: Angiotensin II is mitogenic in neonatal rat cardiac fibroblasts. Circ Res 72: 1245–124, 1993

    Google Scholar 

  9. Crabos M, Roth M, Hahn AWA, Erne P: Characterization of angiotensin II receptors in cultured adult rat cardiac fibroblasts. J Clin Invest 93: 2372–2378, 1994

    Google Scholar 

  10. Villarreal FJ, Kim NN, Ungab GD, Printz MP, Dillmann WH: Identification of functional angiotensin II receptors on rat cardiac fibroblasts. Circulation 88: 2849–2861, 1993

    Google Scholar 

  11. Sadoshima JI, Izumo S: Moleclular characterization of angiotensin II-induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Circ Res 73: 413–423, 1993

    Google Scholar 

  12. Matsubara H, Kanasaki M, Murasawa S, Tsukuguchi Y, Nio Y, Inada M: Differential gene expression and regulation of angiotensin II receptor subtypes in rat cardiac fibroblasts and cardiomyocytes in culture. J Clin Invest 93: 1592–1601, 1994

    Google Scholar 

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

    Google Scholar 

  14. Sechi LA, Griffin CA, Grady EF, Kalinyak JE, Schambelan M: Characterization of angiotensin II receptor subtypes in rat heart. Circ Res 71: 1482–1489, 1992

    Google Scholar 

  15. Brilla CG, Zhou G, Matsubara L, Weber KT: Collagen metabolism in cultured adult rat cardiac fibroblasts: response to angiotensin II and aldosterone. J Mol Cell Cardiol 26: 809–820, 1994

    Google Scholar 

  16. Urata H, Healy B, Stewart RW, Bumpus FM, Husain A: Angiotensin receptors in normal and failing human hearts. J Clin Endocrinol Metab 69: 54–66, 1989

    Google Scholar 

  17. Booz GW, Dostal DE, Baker KM: Regulation of cardiac second messengers by angiotensins. In: K. Lindpaintner, D. Ganten (eds). Cardiac Renin-Angiotensin System (1st edition). New York, Futura, pp 101–124, 1994

    Google Scholar 

  18. Booz GW, Dostal DE, Singer HA, Baker KM: Involvement of Protein Kinase C and Calcium in Angiotensin II-Induced Mitogenesis of Cardiac Fibroblasts. Am J Physiol 267: C1308–1318, 1994

    Google Scholar 

  19. Booz GW, Baker KM: Protein kinase C in angiotensin II signalling in neonatal rat cardiac fibroblasts: Role in the mitogenic response. In: Cardiac Growth and Regeneration. Annals New York Acad Sci 752: 158–167, 1995

  20. Huckel WR, Prokop CA, Dy RC, Herman B, Earp S: Angiotensin II stimulates protein-tyrosine phosphorylation in a calcium-dependent manner Mol Cell Biol 10: 6290–6298, 1990

    Google Scholar 

  21. Schorb W, Peeler TC, Madigan NN, Conrad KM, Baker KM: Angiotensin II-induced protein tyrosine phsophorylation in neonatal rat cardiac fibroblasts. J Biol Chem 269: 19626–19632, 1994

    Google Scholar 

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

    Google Scholar 

  23. Naftilan AJ, Pratt RE, Dzau VJ: Induction of platelet-derived growth factor A-chain and c-myc gene expression by angiotensin II in cultured rat vascular smooth muscle cells. J Clin Invest 83: 1419–1424, 1989

    Google Scholar 

  24. Naftilan AJ, Pratt RE, Eldrige CS, Lin HL, Dzau VJ: Angiotensin II induces c-fos expression in smooth muscle via transcriptional control. Hypertension 13: 706–711, 1989

    Google Scholar 

  25. Paquet JL, Baudouin-Legros M, Brunelle G, Meyer P: Angiotensin II-induced proliferation of aortic myocytes in spontaneously hypertensive rats. J Hypertens 8: 565–572, 1990

    Google Scholar 

  26. Pratt RE, Itoh H, Gibbons, GH, Dzau VJ: Role of angiotensin in the control of vascular smooth muscle growth. J Vasc Med Biol 3: 25–29, 1991

    Google Scholar 

  27. Paxton WG, Marrero MB, Klein JD, Delafontaine P, Berk BC, Bernstein KE: The angiotensin II AT1 receptor is tyrosine and serine phosphorylated and can serve as a substrate for the src family of tyrosine kinases. Biochem Biophys Res Common 200: 260–267, 1994

    Google Scholar 

  28. Booz GW, Conrad KM, Hess AL, Singer HA, Baker KM: Angiotensin II binding sites on hepatocyte nuclei. Endocrinology 130: 3641–3649, 1992

    Google Scholar 

  29. Marrero MB, Paxton WG, Duff JL, Berk BC, Bernstein KE: Angiotensin II stimulates tyrosine phosphorylation of phospholipase C-γ1 in vascular smooth muscle cells. J Biol Chem 269: 10935–10939, 1994

    Google Scholar 

  30. Nakanishi H, Brewer KA, Exton JH: Activation of the ζ isozyme of protein kinase C by phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 268: 13–16, 1993

    Google Scholar 

  31. Wennstrom S, Siegbahn A, Yokote K, Arvidsson AK, Heldin CH, Mori S, Claesson-Welsh L: Membrane ruffling and chemotaxis transduced by the PDGF β-receptor require the binding site for phosphatidylinositol 3′ kinase. Oncogene 9: 651–660, 1994

    Google Scholar 

  32. Lam K, Carpenter CL, Ruderman NB, Friel JC, Kelly KL: The phosphatidylinositol 3-kinase serine kinase phosphorylates IRS-1: Stimulation by insulin and inhibition by wortmannin. J Biol Chem 269: 20648–20652, 1994

    Google Scholar 

  33. Chung J, Grammer TC, Lemon KP, Kazlauskas A, Blenis J: PDGF- and insulin-dependent pp70s6k activation mediated by phosphatidylinositol-3-OH kinase. Nature 370: 71–75, 1994

    Google Scholar 

  34. Ming XF, Burgering BMT, Wennstom S, Claesson-Welsh L, Heldin CH, Bos JL, Kozma SC, Thomas G: Activation of p70/p85 S6 kinase by a pathway independent of p21ras. Nature 371: 426–429, 1994

    Google Scholar 

  35. Rodriguez-Viciana P, Warne PH, Dhand R, Vanhaesebroeck B, Gout I, Fry MJ, Wakefield MD, Downward J: Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370: 527–532, 1994

    Google Scholar 

  36. Sadoshima J, Izumo S: Angiotensin II activates p21ras by tyrosine kinase- and protein kinase C-dependent mechanism in cardiac myocytes. Circulation 88: 1–334, 1993

    Google Scholar 

  37. Zhou G, Wooten MW, Coleman ES: Regulation of atypical ζ-protein kinase C in cellular signaling. Exper Cell Res 214: 1–11, 1994

    Google Scholar 

  38. Disatnik MH, Buraggi G, Mochly-Rosen D: Localization of protein kinase C isozymes in cardiac myocytes. Exper Cell Res 210: 287–297, 1994

    Google Scholar 

  39. Lehrich RW, Forrest JN Jr: Protein kinase C ζ is associated with the mitotic apparatus in primary cell cultures ofthe shark rectal gland. J Biol Chem 269: 32446–32450, 1994

    Google Scholar 

  40. Limatola C, Schapp D, Moolenaar WH, van Blitterswijk WJ: Phosphatidic acid activation of protein kinase C-ζ overexpressed in COS cells: Comparison with other protein kinase C isotypes and other acidic lipids. Biochem J 304: 1001–1008, 1994

    Google Scholar 

  41. Booz GW, Taher MM, Baker KM, Singer HA. Angiotensin II induces phosphatidic acid formation in neonatal rat cardiac fibroblasts: Evaluation of the roles of phospholipases C and D. Mol Cellular Biochem 141: 135–143, 1994

    Google Scholar 

  42. Bhat GJ, Thekkumkara TJ, Thomas WG, Conrad KM, and Baker KM: Angiotensin II stimulates sis-inducing factor-like DNA binding activity: Evidence that the AT1A receptor activates transcription factor p91/or a related protein. J Biol Chem 269: 31443–31449, 1994

    Google Scholar 

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

    Google Scholar 

  44. Bhat GJ, Thekkumkara TJ, Thomas WG, Conrad KM, Baker KM: Activation of the STAT pathway by angiotensin II in T3CHO/AT1A cells: crosstalk between angiotensin II and interleukin-6 nuclear signaling. J Biol Chem 270: 19059–19065, 1995

    Google Scholar 

  45. Gibbons, GH, Pratt RE, Dzau VJ: Vascular smooth muscle cell hypertrophy vs hyperplasia. Autocrine transfoming growth factor-β1 expression determines growth response to angiotensin II. J Clin Invest 90: 456–461, 1992

    Google Scholar 

  46. Fisher SA, Absher M: Norepinephrine and Ang II stimulate secretion of TGF-β by neonatal rat cardiac fibroblasts in vitro. Am J Physiol 268: C910-C917, 1995

    Google Scholar 

  47. Scott-Burden T, Hahn AWA, Resink TJ, Buhler FR: Modulation of extracellular matrix by angiotensin II: stimulated glycoconjugate synthesis and growth in vascular smooth muscle cells. J Cardiovas Pharmacol 16: S36-S41, 1990

    Google Scholar 

  48. Weber KT, Brilla CG: Pathological hypertrophy and cardiac interstitium: fibrobrosis and renin-angiotensin-aldosterone system. Circulation 83: 1849–1865, 1991

    CAS  PubMed  Google Scholar 

  49. Weber KT, Jalil JE, Janicki JS, Pick R: Myocardial collagen remodeling in pressure overload hypertropy; a case for interstitial heart disease. Am J Hypertens 2: 931–940, 1989

    Google Scholar 

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

  51. Mamuya WS, Brecher P: Fibronectin expression in the normal and hypertrophic rat heart. J Clin Invest 89: 392–401, 1992

    Google Scholar 

  52. Linask KK, Lash JW: A role of fibronectin in migration of avain precardial cells, I: dose-dependent effects of fibronectin antibody. Dev Biol 129: 315–323, 1988

    Google Scholar 

  53. van Krimpen C, Smith JFM, Cleutjens JPM, Debets JJM, Schoemaker RG, Struyker HAJ, Bosman FT, Saermaren MJAP: DNA synthesis in the non-infarcted cardiac interstitium after left coronary artery ligation in the rat: effects of captopril. J Mol Cell Cardiol 23: 1245–1253

  54. Sano H, Okada H, Sakata Y, Okamoto H, Kawaguchi H, Yasuda H, Kitabatake A: Angiotensin II potentiates collagen synthesis in the hypertrophied heart. In: Uasuda H. Kawaguchi (ed.). New Aspects in the Treatment of Failing Heart, Springer-Verlag, 1992, pp 199–201

  55. Roberts AB, Sporn MB, Assoian RK, Smith JM, Roche NS, Wakefield LM, Heine UI, Liotta LA, Falanga V, Kehr JH, Fauci AS: Transforming growth factor type B: Rapid induction of fibrosis and angiogensis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci 83: 4167–4171, 1986

    CAS  PubMed  Google Scholar 

  56. Eghbali M, Tomek R, Sukhatme VP, Woods C, Bhambi B: Differential effects of transforming growth factor β1 and phorbol myristate acetate on cardiac fibroblatsts: Regulation of fibrillar collagen mRNA and expression of early transcription factors. Circ Res 69: 483–490, 1991

    Google Scholar 

  57. Matrisian LM, Banser GL, Kerr LD, Pelton RW, Wood LD: Negative regulation of gene expression by TGF-beta. Mol Reprd Dev 32: 111–120, 1992

    Google Scholar 

  58. Raghow R: Role of transforming growth factor-beta in repair and fibrosis. Chest 99: 61S-65S, 1991

    Google Scholar 

  59. Boluyt MO, O'Neill L, Meredith AL, Bing OH, Brooks WW, Conrad CH, Crow MT, Lakatta ET: Alterations in cardiac gene expression during the transition from stable hypertrophy to heart failure. Marked upregulation of genes encoding extracellular matrix components. Circ Res 75: 23–32, 1994

    Google Scholar 

  60. Burgess ML, Carver WE, Terracio L, Wilson SP, Wilson MA, Borg TK: Integrin-mediated collagen gel contraction by cardiac fibroblasts. Effects of angiotensin II. Circ Res 74: 291–298, 1994

    Google Scholar 

  61. Dostal DE, Rothblum KN, Chernin MI, Cooper GR, Baker KM: Intracardiac detection of angiotensinogen and renin: A localized renin-angiotensin system in neonatal rat heart. Am J Physiol 263: C838-C850, 1992

    Google Scholar 

  62. Dostal DE, Rothblum KN, Conrad KM, Cooper GR, Baker KM: Detection of angiotensin I and II in cultured rat cardiac myocytes and fibroblasts. Am J Physiol 263: C851-C863, 1992

    Google Scholar 

  63. Dostal DE, Rothblum KN, Baker KM: An improved method for absolute quantificaiton of mRNA using multiplex polymerase chain reaction: Determination of renin and angiotensinogen mRNA levels in various tissues. Anal Biochem 223: 239–349, 1994

    Google Scholar 

  64. Hirsch A, Talness C, Schunkert H, Paul M, VJD: Tissue-specific activation of cardiac angiotensin converting enzyme in experimental heart failure. Circ Res 69: 475–482, 1991

    Google Scholar 

  65. Lindpaintner K, Lu W, Neidermajer N, Schieffer B, Just H, Ganten D, Drexler H: Selective activation of cardiac angiotensinogen gene expression in post-infarction ventricular remodeling in the rat. J Mol Cell Cardiol 25: 133–143, 1993

    Google Scholar 

  66. Sadoshima J, Takahashi T, Jahn L, Izumo S: Roles of mechanosensitive ion channels, cytoskeleton, and contractile activity in stretch-induced immediate-early gene expression and hypertrophy of cardiac myocytes. Proc Natl Acad Sci USA 89: 9905–9909, 1992

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Weis Center for Research, Geisinger Clinic, 100 North Academy Avenue, 17822-2611, Danville, PA, USA

    David E. Dostal, George W. Booz & Kenneth M. Baker

Authors
  1. David E. Dostal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. George W. Booz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kenneth M. Baker
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dostal, D.E., Booz, G.W. & Baker, K.M. Angiotensin II signalling pathways in cardiac fibroblasts: Conventional versus novel mechanisms in mediating cardiac growth and function. Mol Cell Biochem 157, 15–21 (1996). https://doi.org/10.1007/BF00227876

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00227876

Key words

Search

Navigation