TGF-beta1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II.
Journal: 2002/April - Journal of Clinical Investigation
ISSN: 0021-9738
Abstract:
Angiotensin II (Ang II), a potent hypertrophic stimulus, causes significant increases in TGFb1 gene expression. However, it is not known whether there is a causal relationship between increased levels of TGF-beta1 and cardiac hypertrophy. Echocardiographic analysis revealed that TGF-beta1-deficient mice subjected to chronic subpressor doses of Ang II had no significant change in left ventricular (LV) mass and percent fractional shortening during Ang II treatment. In contrast, Ang II-treated wild-type mice showed a >20% increase in LV mass and impaired cardiac function. Cardiomyocyte cross-sectional area was also markedly increased in Ang II-treated wild-type mice but unchanged in Ang II-treated TGF-beta1-deficient mice. No significant levels of fibrosis, mitotic growth, or cytokine infiltration were detected in Ang II-treated mice. Atrial natriuretic factor expression was approximately 6-fold elevated in Ang II-treated wild-type, but not TGF-beta1-deficient mice. However, the alpha- to beta-myosin heavy chain switch did not occur in Ang II-treated mice, indicating that isoform switching is not obligatorily coupled with hypertrophy or TGF-beta1. The Ang II effect on hypertrophy was shown not to result from stimulation of the endogenous renin-angiotensis system. These results indicate that TGF-beta1 is an important mediator of the hypertrophic growth response of the heart to Ang II.
Relations:
Content
Citations
(125)
References
(73)
Conditions
(1)
Chemicals
(4)
Genes
(1)
Organisms
(4)
Processes
(2)
Anatomy
(2)
Affiliates
(1)
Similar articles
Articles by the same authors
Discussion board
J Clin Invest 109(6): 787-796

TGF-β1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II

Department of Molecular Genetics, Biochemistry, and Microbiology, andDepartment of Pharmacology and Cell Biophysics, Cincinnati College of Medicine, Cincinnati, Ohio, USANoninvasive Cardiac Imaging and Hemodynamic Research Laboratory, Division of Cardiology, Department of Pediatrics, Children’s Hospital Medical Center, Cincinnati, Ohio, USADepartment of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USADepartment of Oral Biology, The Ohio State University, Columbus, Ohio, USA
Address correspondence to: Jo El J. Schultz, Department of Pharmacology and Cell Biophysics, University of Cincinnati, College of Medicine, 231 Albert Sabin Way, ML 0575, Cincinnati, Ohio 45267, USA. Phone: (513) 558-9754; Fax: (513) 558-1169; E-mail: ude.cu.liame@ojluhcs.
Address correspondence to: Jo El J. Schultz, Department of Pharmacology and Cell Biophysics, University of Cincinnati, College of Medicine, 231 Albert Sabin Way, ML 0575, Cincinnati, Ohio 45267, USA. Phone: (513) 558-9754; Fax: (513) 558-1169; E-mail: ude.cu.liame@ojluhcs.
Received 2001 Sep 11; Accepted 2002 Jan 21.

Abstract

Angiotensin II (Ang II), a potent hypertrophic stimulus, causes significant increases in TGFb1 gene expression. However, it is not known whether there is a causal relationship between increased levels of TGF-β1 and cardiac hypertrophy. Echocardiographic analysis revealed that TGF-β1–deficient mice subjected to chronic subpressor doses of Ang II had no significant change in left ventricular (LV) mass and percent fractional shortening during Ang IItreatment. In contrast, Ang II–treated wild-type mice showed a >20% increase in LV mass and impaired cardiac function. Cardiomyocyte cross-sectional area was also markedly increased in Ang II–treated wild-type mice but unchanged in Ang II–treated TGF-β1–deficient mice. No significant levels of fibrosis, mitotic growth, or cytokine infiltration were detected in Ang II–treated mice. Atrial natriuretic factor expression was ∼6-fold elevated in Ang II–treated wild-type, but not TGF-β1–deficient mice. However, the α- to β-myosin heavy chain switch did not occur in Ang II–treated mice, indicating that isoform switching is not obligatorily coupled with hypertrophy or TGF-β1. The Ang IIeffect on hypertrophy was shown not to result from stimulation of the endogenous renin-angiotensis system. These results indicate that TGF-β1 is an important mediator of the hypertrophic growth response of the heart to Ang II.

Abstract

Acknowledgments

This work was supported by grants from the NIH (HL-41496, HL-58511, HD-26470). The investigators acknowledge D. Puthoff for assistance with echocardiographic data; I.E. Ormsby for her excellent animal husbandry work; J.N. Lorenz for the use of blood pressure and flame photometry equipment; G.P. Boivin for pathological reports and for assistance with using the morphometric NIH imaging system; K. Hepner-Goss for assistance with using the fluorescence imaging system; Z. Spicer and D. Millhorn for expert scientific knowledge and technical assistance with the real-time PCR methodology, and R. Banks for critical review of the urinary aldosterone and Na data and manuscript.

Acknowledgments

Footnotes

See the related Commentary beginning on page 715.

Footnotes

References

  • 1. Massague JThe transforming growth factor-beta family. Annu Rev Cell Biol. 1990;6:597–641.[PubMed][Google Scholar]
  • 2. Brand T, Schneider MDThe TGF beta superfamily in myocardium: ligands, receptors, transduction, and function. J Mol Cell Cardiol. 1995;27:5–18.[PubMed][Google Scholar]
  • 3. Kallapur S, Ormsby I, Doetschman TStrain dependency of TGFbeta1 function during embryogenesis. Mol Reprod Dev. 1999;52:341–349.[PubMed][Google Scholar]
  • 4. Dickson MC, et al Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice. Development. 1995;121:1845–1854.[PubMed][Google Scholar]
  • 5. Shull MM, et al Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature. 1992;359:693–699.[Google Scholar]
  • 6. Kulkarni AB, et al Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci USA. 1993;90:770–774.[Google Scholar]
  • 7. Diebold RJ, et al Early-onset multifocal inflammation in the transforming growth factor beta 1-null mouse is lymphocyte mediated. Proc Natl Acad Sci USA. 1995;92:12215–12229.[Google Scholar]
  • 8. D’Souza RN, Litz MAnalysis of tooth development in mice bearing a TGF-beta 1 null mutation. Connect Tissue Res. 1995;32:41–46.[PubMed][Google Scholar]
  • 9. Glick AB, et al Transforming growth factor beta 1 suppresses genomic instability independent of a G1 arrest, p53, and Rb. Cancer Res. 1996;56:3645–3650.[PubMed][Google Scholar]
  • 10. Hoying JB, et al Transforming growth factor beta1 enhances platelet aggregation through a non-transcriptional effect on the fibrinogen receptor. J Biol Chem. 1999;274:31008–31013.[PubMed][Google Scholar]
  • 11. Tang B, et al Transforming growth factor-beta1 is a new form of tumor suppressor with true haploid insufficiency. Nat Med. 1998;4:802–807.[PubMed][Google Scholar]
  • 12. Glick AB, et al Targeted deletion of the TGF-beta 1 gene causes rapid progression to squamous cell carcinoma. Genes Dev. 1994;8:2429–2440.[PubMed][Google Scholar]
  • 13. Engle SJ, et al Transforming growth factor beta1 suppresses nonmetastatic colon cancer at an early stage of tumorigenesis. Cancer Res. 1999;59:3379–3386.[PubMed][Google Scholar]
  • 14. Thompson NL, et al Transforming growth factor beta-1 in acute myocardial infarction in rats. Growth Factors. 1988;1:91–99.[PubMed][Google Scholar]
  • 15. Eghbali MCellular origin and distribution of transforming growth factor-beta in the normal rat myocardium. Cell Tissue Res. 1989;256:553–558.[PubMed][Google Scholar]
  • 16. Takahashi N, et al Hypertrophic stimuli induce transforming growth factor-beta 1 expression in rat ventricular myocytes. J Clin Invest. 1994;94:1470–1476.[Google Scholar]
  • 17. Li RK, et al Overexpression of transforming growth factor-beta1 and insulin-like growth factor-I in patients with idiopathic hypertrophic cardiomyopathy. Circulation. 1997;96:874–881.[PubMed][Google Scholar]
  • 18. Li G, et al. Elevated insulin-like growth factor-I and transforming growth factor- beta 1 and their receptors in patients with idiopathic hypertrophic obstructive cardiomyopathy. A possible mechanism. Circulation. 1998;98(Suppl. 19):II144–II149.[PubMed]
  • 19. Millan FA, Denhez F, Kondaiah P, Akhurst RJEmbryonic gene expression patterns of TGF beta 1, beta 2 and beta 3 suggest different developmental functions in vivo. Development. 1991;111:131–143.[PubMed][Google Scholar]
  • 20. Pelton RW, Saxena B, Jones M, Moses HL, Gold LIImmunohistochemical localization of TGF beta 1, TGF beta 2, and TGF beta 3 in the mouse embryo: expression patterns suggest multiple roles during embryonic development. J Cell Biol. 1991;115:1091–1105.[Google Scholar]
  • 21. MacLellan WR, Brand T, Schneider MDTransforming growth factor-beta in cardiac ontogeny and adaptation. Circ Res. 1993;73:783–791.[PubMed][Google Scholar]
  • 22. Eghbali M, Tomek R, Sukhatme VP, Woods C, Bhambi B. Differential effects of transforming growth factor-beta 1 and phorbol myristate acetate on cardiac fibroblasts. Regulation of fibrillar collagen mRNAs and expression of early transcription factors. Circ Res. 1991;69:483–490.[PubMed]
  • 23. Villarreal FJ, Dillmann WHCardiac hypertrophy-induced changes in mRNA levels for TGF-beta 1, fibronectin, and collagen. Am J Physiol. 1992;262:H1861–H1866.[PubMed][Google Scholar]
  • 24. Kupfahl C, et al Angiotensin II directly increases transforming growth factor beta1 and osteopontin and indirectly affects collagen mRNA expression in the human heart. Cardiovasc Res. 2000;46:463–475.[PubMed][Google Scholar]
  • 25. Parker TG, Packer SE, Schneider MDPeptide growth factors can provoke “fetal” contractile protein gene expression in rat cardiac myocytes. J Clin Invest. 1990;85:507–514.[Google Scholar]
  • 26. Schultz JE, et al Fibroblast growth factor-2 mediates pressure-induced hypertrophic response. J Clin Invest. 1999;104:709–719.[Google Scholar]
  • 27. Tiret L, et al Lack of association between polymorphisms of eight candidate genes and idiopathic dilated cardiomyopathy: the CARDIGENE study. J Am Coll Cardiol. 2000;35:29–35.[PubMed][Google Scholar]
  • 28. Patel R, et al Variants of trophic factors and expression of cardiac hypertrophy in patients with hypertrophic cardiomyopathy. J Mol Cell Cardiol. 2000;32:2369–2377.[PubMed][Google Scholar]
  • 29. Gray MO, Long CS, Kalinyak JE, Li HT, Karliner JSAngiotensin II stimulates cardiac myocyte hypertrophy via paracrine release of TGF-beta 1 and endothelin-1 from fibroblasts. Cardiovasc Res. 1998;40:352–363.[PubMed][Google Scholar]
  • 30. Lee AA, Dillmann WH, McCulloch AD, Villarreal FJAngiotensin II stimulates the autocrine production of transforming growth factor-beta 1 in adult rat cardiac fibroblasts. J Mol Cell Cardiol. 1995;27:2347–2357.[PubMed][Google Scholar]
  • 31. Sadoshima J, Izumo S. Molecular characterization of angiotensin II-induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Critical role of the AT1 receptor subtype. Circ Res. 1993;73:413–423.[PubMed]
  • 32. Everett AD, Tufro-McReddie A, Fisher A, Gomez RAAngiotensin receptor regulates cardiac hypertrophy and transforming growth factor-beta 1 expression. Hypertension. 1994;23:587–592.[PubMed][Google Scholar]
  • 33. Ichihara S, et al Angiotensin II type 2 receptor is essential for left ventricular hypertrophy and cardiac fibrosis in chronic angiotensin II-induced hypertension. Circulation. 2001;104:346–351.[PubMed][Google Scholar]
  • 34. Schatz DG, Oettinger MA, Baltimore DThe V(D)J recombination activating gene, RAG-1. Cell. 1989;59:1035–1048.[PubMed][Google Scholar]
  • 35. Harada K, et al Pressure overload induces cardiac hypertrophy in angiotensin II type 1A receptor knockout mice. Circulation. 1998;97:1952–1959.[PubMed][Google Scholar]
  • 36. Williams RV, et al End-systolic stress-velocity and pressure-dimension relationships by transthoracic echocardiography in mice. Am J Physiol. 1998;274:H1828–H1835.[PubMed][Google Scholar]
  • 37. Sahn DJ, DeMaria A, Kisslo J, Weyman ARecommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation. 1978;58:1072–1083.[PubMed][Google Scholar]
  • 38. Thoss K, Roth J. The use of fluorescein isothiocyanate labeled lectins for immuno-histological demonstration of saccharides. III. Studies by use of Ricinus communislectin and wheat germ agglutinin. Exp Pathol (Jena) 1977;14:215–219.[PubMed]
  • 39. D’Angelo DD, et al Transgenic Galphaq overexpression induces cardiac contractile failure in mice. Proc Natl Acad Sci USA. 1997;94:8121–8126.[Google Scholar]
  • 40. Seta KA, Kim R, Kim HW, Millhorn DE, Beitner-Johnson DHypoxia-induced regulation of MAPK phosphatase-1 as identified by subtractive suppression hybridization and cDNA microarray analysis. J Biol Chem. 2001;276:44405–44412.[PubMed][Google Scholar]
  • 41. Reiser PJ, Kline WOElectrophoretic separation and quantitation of cardiac myosin heavy chain isoforms in eight mammalian species. Am J Physiol. 1998;274:H1048–H1053.[PubMed][Google Scholar]
  • 42. Rogers WJ, et al Comparison of indices of muscle and pump performance in patients with coronary artery disease. Cathet Cardiovasc Diagn. 1975;1:17–34.[PubMed][Google Scholar]
  • 43. Osher J, et al. Methylprednisolone treatment in acute myocardial infarction. Effect on regional and global myocardial function. Am J Cardiol. 1976;37:564–571.[PubMed]
  • 44. Wood MA, Ellenbogen KA, Kapadia K, Lu B, Valenta HComparison of right ventricular impedance, pulse pressure and maximal dP/dt for determination of hemodynamic stability of ventricular arrhythmias associated with coronary artery disease. Am J Cardiol. 1990;66:575–582.[PubMed][Google Scholar]
  • 45. Bolognesi R, et al Detection of early abnormalities of left ventricular function by hemodynamic, echo-tissue Doppler imaging, and mitral Doppler flow techniques in patients with coronary artery disease and normal ejection fraction. J Am Soc Echocardiogr. 2001;14:764–772.[PubMed][Google Scholar]
  • 46. Boivin GP, et al Onset and progression of pathological lesions in transforming growth factor-beta 1-deficient mice. Am J Pathol. 1995;146:276–288.[Google Scholar]
  • 47. Kulkarni AB, et al. Transforming growth factor-beta 1 null mice. An animal model for inflammatory disorders. Am J Pathol. 1995;146:264–275.
  • 48. Brody MJNew developments in our knowledge of blood pressure regulation. Fed Proc. 1981;40:2257–2261.[PubMed][Google Scholar]
  • 49. Reid IAActions of angiotensin II on the brain: mechanisms and physiologic role. Am J Physiol. 1984;246:F533–F543.[PubMed][Google Scholar]
  • 50. Yang G, Wan Y, Zhu YAngiotensin II—an important stress hormone. Biol Signals. 1996;5:1–8.[PubMed][Google Scholar]
  • 51. Chan JCControl of aldosterone secretion. Nephron. 1979;23:79–83.[PubMed][Google Scholar]
  • 52. Garty HRegulation of the epithelial Na+ channel by aldosterone: open questions and emerging answers. Kidney Int. 2000;57:1270–1276.[PubMed][Google Scholar]
  • 53. Silberbach M, Roberts CT., Jr Natriuretic peptide signalling: molecular and cellular pathways to growth regulation. Cell Signal. 2001;13:221–231.[PubMed]
  • 54. Buttrick PM, Kaplan M, Leinwand LA, Scheuer JAlterations in gene expression in the rat heart after chronic pathological and physiological loads. J Mol Cell Cardiol. 1994;26:61–67.[PubMed][Google Scholar]
  • 55. Calderone A, Murphy RJ, Lavoie J, Colombo F, Beliveau LTGF-beta(1) and prepro-ANP mRNAs are differentially regulated in exercise-induced cardiac hypertrophy. J Appl Physiol. 2001;91:771–776.[PubMed][Google Scholar]
  • 56. Ruwhof C, van Wamel AE, Egas JM, van der Laarse ACyclic stretch induces the release of growth promoting factors from cultured neonatal cardiomyocytes and cardiac fibroblasts. Mol Cell Biochem. 2000;208:89–98.[PubMed][Google Scholar]
  • 57. Kim NN, Villarreal FJ, Printz MP, Lee AA, Dillmann WHTrophic effects of angiotensin II on neonatal rat cardiac myocytes are mediated by cardiac fibroblasts. Am J Physiol. 1995;269:E426–E437.[PubMed][Google Scholar]
  • 58. Knowles JW, et al Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A-deficient mice. J Clin Invest. 2001;107:975–984.[Google Scholar]
  • 59. Omura T, Kim S, Takeuchi K, Iwao H, Takeda TTransforming growth factor beta 1 and extracellular matrix gene expression in isoprenaline induced cardiac hypertrophy: effects of inhibition of the renin-angiotensin system. Cardiovasc Res. 1994;28:1835–1842.[PubMed][Google Scholar]
  • 60. Nakajima H, et al Atrial but not ventricular fibrosis in mice expressing a mutant transforming growth factor-beta(1) transgene in the heart. Circ Res. 2000;86:571–579.[PubMed][Google Scholar]
  • 61. Lompre AM, et al Myosin isoenzyme redistribution in chronic heart overload. Nature. 1979;282:105–107.[PubMed][Google Scholar]
  • 62. Mercadier JJ, et al Myosin isoenzyme changes in several models of rat cardiac hypertrophy. Circ Res. 1981;49:525–532.[PubMed][Google Scholar]
  • 63. Tsuchimochi H, et al. Isozymic changes in myosin of human atrial myocardium induced by overload. Immunohistochemical study using monoclonal antibodies. J Clin Invest. 1984;74:662–665.
  • 64. Lompre AM, Mercadier JJ, Schwartz KChanges in gene expression during cardiac growth. Int Rev Cytol. 1991;124:137–186.[PubMed][Google Scholar]
  • 65. Schneider MD, Parker TGCardiac myocytes as targets for the action of peptide growth factors. Circulation. 1990;81:1443–1456.[PubMed][Google Scholar]
  • 66. Parker TG, Schneider MDGrowth factors, proto-oncogenes, and plasticity of the cardiac phenotype. Annu Rev Physiol. 1991;53:179–200.[PubMed][Google Scholar]
  • 67. Parker TG, Chow KL, Schwartz RJ, Schneider MDTGF-beta 1 and fibroblast growth factors selectively up-regulate tissue-specific fetal genes in cardiac muscle cells. Ciba Found Symp. 1991;157:152–160.[PubMed][Google Scholar]
  • 68. Mercadier JJ, et al Myosin isoenzymes in normal and hypertrophied human ventricular myocardium. Circ Res. 1983;53:52–62.[PubMed][Google Scholar]
  • 69. Susic D, Nunez E, Frohlich ED, Prakash OAngiotensin II increases left ventricular mass without affecting myosin isoform mRNAs. Hypertension. 1996;28:265–268.[PubMed][Google Scholar]
  • 70. Bauer EP, Kuki S, Zimmermann R, Schaper WUpregulated and downregulated transcription of myocardial genes after pulmonary artery banding in pigs. Ann Thorac Surg. 1998;66:527–531.[PubMed][Google Scholar]
  • 71. Vikstrom KL, Bohlmeyer T, Factor SM, Leinwand LAHypertrophy, pathology, and molecular markers of cardiac pathogenesis. Circ Res. 1998;82:773–778.[PubMed][Google Scholar]
  • 72. Sadoshima J, Izumo S. Rapamycin selectively inhibits angiotensin II-induced increase in protein synthesis in cardiac myocytes in vitro. Potential role of 70-kD S6 kinase in angiotensin II-induced cardiac hypertrophy. Circ Res. 1995;77:1040–1052.[PubMed]
  • 73. Izumo S, et al. Myosin heavy chain messenger RNA and protein isoform transitions during cardiac hypertrophy. Interaction between hemodynamic and thyroid hormone-induced signals. J Clin Invest. 1987;79:970–977.
Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.