Skip to main content

Advertisement

Springer Nature Link
Log in

Transforming growth factor beta inhibition increases mortality and left ventricular dilatation after myocardial infarction

  • ORIGINAL CONTRIBUTION
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

Background

Transforming growth factor (TGF)-β is a locally generated cytokine involved in healing processes and tissue fibrosis, all relevant for cardiac remodeling and the development of heart failure after myocardial infarction (MI). However, data regarding the function of TGF-β after ischemic injury are inconclusive.

Methods and results

We tested the effect of TGF-β inhibition by application of a blocking antibody in mice with MI. Starting 1 week before or 5 days after coronary artery ligation mice were treated with intraperitoneal injections of an anti-TGF-β (5 mg/kg bodyweight 1D11, Genzyme) or control antibody. Mortality over 8 weeks was significantly higher in the groups treated with the anti-TGF-β antibody. Both, pre or post MI treatments were associated with increased left ventricular dilatation after MI as determined by serial echocardiography. In anti-TGF-β treated mice collagen production decreased and matrix-metalloproteinase expression increased. However, the expression of TGF pro-inflammatory cytokine TNF-α was not altered by the treatment.

Summary

Anti-TGF-β treatment before or after coronary artery ligation increases mortality and worsens left ventricular remodeling in mice with non-reperfused MI. The detrimental effects of TGF-β inhibition may be mediated by alterations in extracellular matrix remodeling.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Border WA, Noble NA (1994) Transforming growth factor beta in tissue fibrosis. N Engl J Med 331:1286–1292

    Article  PubMed  CAS  Google Scholar 

  2. Brooks WW, Conrad CH (2000) Myocardial fibrosis in transforming growth factor beta(1)heterozygous mice. J Mol Cell Cardiol 32:187–195

    Article  PubMed  CAS  Google Scholar 

  3. Bujak M, Frangogiannis NG (2007) The role of TGF-beta signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res 74:184–195

    Article  PubMed  CAS  Google Scholar 

  4. Dasch JR, Pace DR, Waegell W, Inenaga D, Ellingsworth L (1989) Monoclonal antibodies recognizing transforming growth factor-beta. Bioactivity neutralization and transforming growth factor beta 2 affinity purification. J Immunol 142:1536–1541

    PubMed  CAS  Google Scholar 

  5. Deten A, Holzl A, Leicht M, Barth W, Zimmer HG (2001) Changes in extracellular matrix and in transforming growth factor beta isoforms after coronary artery ligation in rats. J Mol Cell Cardiol 33:1191–1207

    Article  PubMed  CAS  Google Scholar 

  6. Ducharme A, Frantz S, Aikawa M, Rabkin E, Lindsey M, Rohde LE, Schoen FJ, Kelly RA, Werb Z, Libby P, Lee RT (2000) Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction. J Clin Invest 106:55–62

    Article  PubMed  CAS  Google Scholar 

  7. Ertl G, Frantz S (2005) Healing after myocardial infarction. Cardiovasc Res 66:22–32

    Article  PubMed  CAS  Google Scholar 

  8. Fischer P, Hilfiker-Kleiner D (2007) Survival pathways in hypertrophy and heart failure: the gp130-STAT axis. Basic Res Cardiol 102:393–411

    Article  PubMed  CAS  Google Scholar 

  9. Frantz S, Ducharme A, Sawyer D, Rohde LE, Kobzik L, Fukazawa R, Tracey D, Allen H, Lee RT, Kelly RA (2003) Targeted deletion of caspase-1 reduces early mortality and left ventricular dilatation following myocardial infarction. J Mol Cell Cardiol 35:685–694

    Article  PubMed  CAS  Google Scholar 

  10. Frantz S, Fraccarollo D, Wagner H, Behr TM, Jung P, Angermann CE, Ertl G, Bauersachs J (2003) Sustained activation of nuclear factor kappa B and activator protein 1 in chronic heart failure. Cardiovasc Res 57:749–756

    Article  PubMed  CAS  Google Scholar 

  11. Frantz S, Hu K, Bayer B, Gerondakis S, Strotmann J, Adamek A, Ertl G, Bauersachs J (2006) Absence of NF-kappaB subunit p50 improves heart failure after myocardial infarction. FASEB J 20:1918–1920

    Article  PubMed  CAS  Google Scholar 

  12. Frantz S, Hu K, Widder J, Bayer B, Witzel CC, Schmidt I, Galuppo P, Strotmann J, Ertl G, Bauersachs J (2004) Peroxisome proliferator activated-receptor agonism and left ventricular remodeling in mice with chronic myocardial infarction. Br J Pharmacol 141:9–14

    Article  PubMed  CAS  Google Scholar 

  13. Frantz S, Kobzik L, Kim YD, Fukazawa R, Medzhitov R, Lee RT, Kelly RA (1999) Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium. J Clin Invest 104:271–280

    Article  PubMed  CAS  Google Scholar 

  14. Friehs I, Margossian RE, Moran AM, Cao-Danh H, Moses MA, del Nido PJ (2006) Vascular endothelial growth factor delays onset of failure in pressure-overload hypertrophy through matrix metalloproteinase activation and angiogenesis. Basic Res Cardiol 101:204–213

    Article  PubMed  CAS  Google Scholar 

  15. Ikeuchi M, Tsutsui H, Shiomi T, Matsusaka H, Matsushima S, Wen J, Kubota T, Takeshita A (2004) Inhibition of TGF-beta signaling exacerbates early cardiac dysfunction but prevents late remodeling after infarction. Cardiovasc Res 64:526–535

    Article  PubMed  CAS  Google Scholar 

  16. Khanna AK, Plummer MS, Hilton G, Pieper GM, Ledbetter S (2004) Anti-transforming growth factor antibody at low but not high doses limits cyclosporine-mediated nephrotoxicity without altering rat cardiac allograft survival: potential of therapeutic applications. Circulation 110:3822–3829

    Article  PubMed  CAS  Google Scholar 

  17. Kuwahara F, Kai H, Tokuda K, Kai M, Takeshita A, Egashira K, Imaizumi T (2002) Transforming growth factor-beta function blocking prevents myocardial fibrosis and diastolic dysfunction in pressure-overloaded rats. Circulation 106:130–135

    Article  PubMed  CAS  Google Scholar 

  18. Ling H, Li X, Jha S, Wang W, Karetskaya L, Pratt B, Ledbetter S (2003) Therapeutic role of TGF-beta-neutralizing antibody in mouse cyclosporin A nephropathy: morphologic improvement associated with functional preservation. J Am Soc Nephrol 14:377–388

    Article  PubMed  CAS  Google Scholar 

  19. Mackey AL, Donnelly AE, Turpeenniemi-Hujanen T, Roper HP (2004) Skeletal muscle collagen content in humans after high-force eccentric contractions. J Appl Physiol 97:197–203

    Article  PubMed  CAS  Google Scholar 

  20. Mehta JL, Chen HJ, Li DY (2002) Protection of myocytes from hypoxia-reoxygenation injury by nitric oxide is mediated by modulation of transforming growth factor-beta1. Circulation 105:2206–2211

    Article  PubMed  CAS  Google Scholar 

  21. Mitchell GF, Jeron A, Koren G (1998) Measurement of heart rate and Q–T interval in the conscious mouse. Am J Physiol 274:H747–H751

    PubMed  CAS  Google Scholar 

  22. Nahrendorf M, Hu K, Frantz S, Jaffer FA, Tung CH, Hiller KH, Voll S, Nordbeck P, Sosnovik D, Gattenlohner S, Novikov M, Dickneite G, Reed GL, Jakob P, Rosenzweig A, Bauer WR, Weissleder R, Ertl G (2006) Factor XIII deficiency causes cardiac rupture, impairs wound healing, and aggravates cardiac remodeling in mice with myocardial infarction. Circulation 113:1196–1202

    Article  PubMed  CAS  Google Scholar 

  23. Nakajima H, Nakajima HO, Salcher O, Dittie AS, Dembowsky K, Jing S, Field LJ (2000) Atrial but not ventricular fibrosis in mice expressing a mutant transforming growth factor-beta(1) transgene in the heart. Circ Res 86:571–579

    PubMed  CAS  Google Scholar 

  24. Nwogu JI, Geenen D, Bean M, Brenner MC, Huang X, Buttrick PM (2001) Inhibition of collagen synthesis with prolyl 4-hydroxylase inhibitor improves left ventricular function and alters the pattern of left ventricular dilatation after myocardial infarction. Circulation 104:2216–2221

    Article  PubMed  CAS  Google Scholar 

  25. Okada H, Takemura G, Kosai K, Li Y, Takahashi T, Esaki M, Yuge K, Miyata S, Maruyama R, Mikami A, Minatoguchi S, Fujiwara T, Fujiwara H (2005) Postinfarction gene therapy against transforming growth factor-beta signal modulates infarct tissue dynamics and attenuates left ventricular remodeling and heart failure. Circulation 111:2430–2437

    Article  PubMed  CAS  Google Scholar 

  26. Pfeffer JM, Pfeffer MA, Braunwald E (1985) Influence of chronic captopril therapy on the infarcted left ventricle of the rat. Circ Res 57:84–95

    PubMed  CAS  Google Scholar 

  27. Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ, Jr., Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, et al. (1992) Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med 327:669–677

    PubMed  CAS  Google Scholar 

  28. Rosenkranz S (2004) TGF-beta1 and angiotensin networking in cardiac remodeling. Cardiovasc Res 63:423–432

    Article  PubMed  CAS  Google Scholar 

  29. Sakata Y, Chancey AL, Divakaran VG, Sekiguchi K, Sivasubramanian N, Mann DL (2008) Transforming growth factor-beta receptor antagonism attenuates myocardial fibrosis in mice with cardiac-restricted overexpression of tumor necrosis factor. Basic Res Cardiol 103:60–68

    Article  PubMed  CAS  Google Scholar 

  30. Sanderson N, Factor V, Nagy P, Kopp J, Kondaiah P, Wakefield L, Roberts AB, Sporn MB, Thorgeirsson SS (1995) Hepatic expression of mature transforming growth factor beta 1 in transgenic mice results in multiple tissue lesions. Proc Natl Acad Sci USA 92:2572–2576

    Article  PubMed  CAS  Google Scholar 

  31. Schultz Jel J, Witt SA, Glascock BJ, Nieman ML, Reiser PJ, Nix SL, Kimball TR, Doetschman T (2002) TGF-beta1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II. J Clin Invest 109:787–796

    PubMed  Google Scholar 

  32. Skyschally A, Leineweber K, Gres P, Haude M, Erbel R, Heusch G (2006) Coronary microembolization. Basic Res Cardiol 101:373–382

    Article  PubMed  Google Scholar 

  33. Van Linthout S, Seeland U, Riad A, Eckhardt O, Hohl M, Dhayat N, Richter U, Fischer JW, Bohm M, Pauschinger M, Schultheiss HP, Tschope C (2008) Reduced MMP-2 activity contributes to cardiac fibrosis in experimental diabetic cardiomyopathy. Basic Res Cardiol 103:319–327

    Google Scholar 

  34. Vanhoutte D, Schellings M, Pinto Y, Heymans S (2006) Relevance of matrix metalloproteinases and their inhibitors after myocardial infarction: a temporal and spatial window. Cardiovasc Res 69:604–613

    Article  PubMed  CAS  Google Scholar 

  35. Wang J, Xu N, Feng X, Hou N, Zhang J, Cheng X, Chen Y, Zhang Y, Yang X (2005) Targeted disruption of Smad4 in cardiomyocytes results in cardiac hypertrophy and heart failure. Circ Res 97:821–828

    Article  PubMed  CAS  Google Scholar 

  36. Westermann D, Van Linthout S, Dhayat S, Dhayat N, Schmidt A, Noutsias M, Song XY, Spillmann F, Riad A, Schultheiss HP, Tschope C (2007) Tumor necrosis factor-alpha antagonism protects from myocardial inflammation and fibrosis in experimental diabetic cardiomyopathy. Basic Res Cardiol 102:500–507

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by a grant from the Deutsche Forschungsgemeinschaft (SFB 688, TP A10) and by Genyzme Corporation, Framingham, MA, USA.

Author information

Authors and Affiliations

  1. Medizinische Klinik und Poliklinik I, Herz-/Kreislaufzentrum, Universitätsklinikum Würzburg, Josef Schneider-Straße 2, 97080, Würzburg, Germany

    Stefan Frantz MD, Kai Hu, Anna Adamek, Jürgen Wolf, Abed Sallam, Sebastian KG Maier, Georg Ertl & Johann Bauersachs

  2. Genzyme Corporation, Framingham, MA, USA

    Scott Lonning & Hong Ling

Authors
  1. Stefan Frantz MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kai Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anna Adamek
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jürgen Wolf
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Abed Sallam
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sebastian KG Maier
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Scott Lonning
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hong Ling
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Georg Ertl
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Johann Bauersachs
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stefan Frantz MD.

Additional information

Returned for 1. Revision: 2 January 2008 1. Revision received: 18 April 2008

Returned for 2. Revision: 14 May 2008 2. Revision received: 19 May 2008

Returned for 3. Revision: 19 June 2008 3. Revision received: 24 June 2008

Rights and permissions

Reprints and permissions

About this article

Cite this article

Frantz, S., Hu, K., Adamek, A. et al. Transforming growth factor beta inhibition increases mortality and left ventricular dilatation after myocardial infarction. Basic Res Cardiol 103, 485–492 (2008). https://doi.org/10.1007/s00395-008-0739-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00395-008-0739-7

Keywords

Search

Navigation