Skip to main content

Advertisement

SpringerLink
Log in

Cardiac fibroblasts support cardiac inflammation in heart failure

  • Original Contribution
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

Cardiac remodeling and inflammation are hallmarks of cardiac failure and correlate with outcome in patients. However, the basis for the development of both remains unclear. We have previously reported that cardiac inflammation triggers transdifferentiation of fibroblasts to myofibroblasts and therefore increase accumulation of cardiac collagen, one key pathology in cardiac remodeling. Hence, identifying key pathways for inflammation would be beneficial for patients suffering from heart failure also. Besides their well-characterized function in matrix regulation, we here investigate the role of fibroblasts in the inflammatory process. We address for the first time the role of fibroblasts as inflammatory supporter cells in heart failure. Using endomyocardial biopsies from patients with heart failure and dilated cardiomyopathy, we created a primary human cardiac fibroblast cell culture system. We found that mechanical stretch mimicking cardiac dilation in heart failure induces activation of fibroblasts and not only stimulates production of extracellular matrix but more interestingly up-regulates chemokine production and triggers typical inflammatory pathways in vitro. Moreover, the cell culture supernatant of stretched fibroblasts activates inflammatory cells and induces further recruitment of monocytes by allowing transendothelial migration into the cardiac tissue. Our findings reveal that cardiac fibroblasts provide pro-inflammatory mediators and may act as sentinel cells activated by mechanical stress. Those cells are able to recruit inflammatory cells into the cardiac tissue, a process known to aggravate outcome of patients. This might be important in different forms of heart failure and therefore may be one general mechanism specific for fibroblasts.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Babelova A, Moreth K, Tsalastra-Greul W, Zeng-Brouwers J, Eickelberg O, Young MF, Bruckner P, Pfeilschifter J, Schaefer RM, Grone HJ, Schaefer L (2009) Biglycan, a danger signal that activates the NLRP3 inflammasome via toll-like and P2X receptors. J Biol Chem 284:24035–24048. doi:10.1074/jbc.M109.014266

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  2. Barczyk M, Carracedo S, Gullberg D (2010) Integrins. Cell Tissue Res 339:269–280. doi:10.1007/s00441-009-0834-6

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  3. Bradley LM, Douglass MF, Chatterjee D, Akira S, Baaten BJ (2012) Matrix metalloprotease 9 mediates neutrophil migration into the airways in response to influenza virus-induced toll-like receptor signaling. PLoS Pathog 8:e1002641. doi:10.1371/journal.ppat.1002641

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  4. Dobaczewski M, Gonzalez-Quesada C, Frangogiannis NG (2010) The extracellular matrix as a modulator of the inflammatory and reparative response following myocardial infarction. J Mol Cell Cardiol 48:504–511. doi:10.1016/j.yjmcc.2009.07.015

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. Duerrschmid C, Crawford JR, Reineke E, Taffet GE, Trial J, Entman ML, Haudek SB (2013) TNF receptor 1 signaling is critically involved in mediating angiotensin-II-induced cardiac fibrosis. J Mol Cell Cardiol 57:59–67. doi:10.1016/j.yjmcc.2013.01.006

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. Frangogiannis NG (2012) Regulation of the inflammatory response in cardiac repair. Circ Res 110:159–173. doi:10.1161/CIRCRESAHA.111.243162

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  7. Fujiu K, Nagai R (2013) Contributions of cardiomyocyte-cardiac fibroblast-immune cell interactions in heart failure development. Basic Res Cardiol 108:357. doi:10.1007/s00395-013-0357-x

    Article  PubMed  Google Scholar 

  8. Gidday JM, Gasche YG, Copin JC, Shah AR, Perez RS, Shapiro SD, Chan PH, Park TS (2005) Leukocyte-derived matrix metalloproteinase-9 mediates blood-brain barrier breakdown and is proinflammatory after transient focal cerebral ischemia. Am J Physiol Heart Circ Physiol 289:H558–H568. doi:10.1152/ajpheart.01275.2004

    Article  PubMed  CAS  Google Scholar 

  9. Hamilton TA, Ohmori Y, Tebo J (2002) Regulation of chemokine expression by anti-inflammatory cytokines. Immunol Res 25:229–245. doi:10.1385/IR:25:3:229

    Article  PubMed  CAS  Google Scholar 

  10. Hawwa RL, Hokenson MA, Wang Y, Huang Z, Sharma S, Sanchez-Esteban J (2011) IL-10 inhibits inflammatory cytokines released by fetal mouse lung fibroblasts exposed to mechanical stretch. Pediatr Pulmonol 46:640–649. doi:10.1002/ppul.21433

    Article  PubMed  PubMed Central  Google Scholar 

  11. Hazebroek M, Dennert R, Heymans S (2012) Idiopathic dilated cardiomyopathy: possible triggers and treatment strategies. Neth Heart J 20:332–335. doi:10.1007/s12471-012-0285-7

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Herum KM, Lunde IG, Skrbic B, Florholmen G, Behmen D, Sjaastad I, Carlson CR, Gomez MF, Christensen G (2013) Syndecan-4 signaling via NFAT regulates extracellular matrix production and cardiac myofibroblast differentiation in response to mechanical stress. J Mol Cell Cardiol 54:73–81. doi:10.1016/j.yjmcc.2012.11.006

    Article  PubMed  CAS  Google Scholar 

  13. Heymans S, Hirsch E, Anker SD, Aukrust P, Balligand JL, Cohen-Tervaert JW, Drexler H, Filippatos G, Felix SB, Gullestad L, Hilfiker-Kleiner D, Janssens S, Latini R, Neubauer G, Paulus WJ, Pieske B, Ponikowski P, Schroen B, Schultheiss HP, Tschope C, Van Bilsen M, Zannad F, McMurray J, Shah AM (2009) Inflammation as a therapeutic target in heart failure? A scientific statement from the Translational Research Committee of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 11:119–129. doi:10.1093/eurjhf/hfn043

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  14. Hofmann U, Frantz S (2013) How can we cure a heart “in flame”? A translational view on inflammation in heart failure. Basic Res Cardiol 108:356. doi:10.1007/s00395-013-0356-y

    Article  PubMed  PubMed Central  Google Scholar 

  15. Husse B, Briest W, Homagk L, Isenberg G, Gekle M (2007) Cyclical mechanical stretch modulates expression of collagen I and collagen III by PKC and tyrosine kinase in cardiac fibroblasts. Am J Physiol Regul Integr Comp Physiol 293:R1898–R1907. doi:10.1152/ajpregu.00804.2006

    Article  PubMed  CAS  Google Scholar 

  16. Kasner M, Westermann D, Lopez B, Gaub R, Escher F, Kuhl U, Schultheiss HP, Tschope C (2011) Diastolic tissue Doppler indexes correlate with the degree of collagen expression and cross-linking in heart failure and normal ejection fraction. J Am Coll Cardiol 57:977–985. doi:10.1016/j.jacc.2010.10.024

    Article  PubMed  CAS  Google Scholar 

  17. Kindermann I, Kindermann M, Kandolf R, Klingel K, Bultmann B, Muller T, Lindinger A, Bohm M (2008) Predictors of outcome in patients with suspected myocarditis. Circulation 118:639–648. doi:10.1161/CIRCULATIONAHA.108.769489

    Article  PubMed  Google Scholar 

  18. Leitinger B (2011) Transmembrane collagen receptors. Annu Rev Cell Dev Biol 27:265–290. doi:10.1146/annurev-cellbio-092910-154013

    Article  PubMed  CAS  Google Scholar 

  19. Lindner D, Zietsch C, Becher PM, Schulze K, Schultheiss HP, Tschope C, Westermann D (2012) Differential expression of matrix metalloproteases in human fibroblasts with different origins. Biochem Res Int 2012:875742. doi:10.1155/2012/875742

    Article  PubMed  PubMed Central  Google Scholar 

  20. Liu SF, Ye X, Malik AB (1999) Inhibition of NF-kappaB activation by pyrrolidine dithiocarbamate prevents In vivo expression of proinflammatory genes. Circulation 100:1330–1337. doi:10.1161/01.CIR.100.12.1330

    Article  PubMed  CAS  Google Scholar 

  21. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2 (-Delta Delta C(T)) Method. Methods 25:402–408. doi:10.1006/meth.2001.1262

    Article  PubMed  CAS  Google Scholar 

  22. Nastase MV, Young MF, Schaefer L (2012) Biglycan: a multivalent proteoglycan providing structure and signals. J Histochem Cytochem 60:963–975. doi:10.1369/0022155412456380

    Article  PubMed  PubMed Central  Google Scholar 

  23. Papakrivopoulou J, Lindahl GE, Bishop JE, Laurent GJ (2004) Differential roles of extracellular signal-regulated kinase 1/2 and p38MAPK in mechanical load-induced procollagen alpha1(I) gene expression in cardiac fibroblasts. Cardiovasc Res 61:736–744. doi:10.1016/j.cardiores.2003.12.018

    Article  PubMed  CAS  Google Scholar 

  24. Spinale FG, Zile MR (2013) Integrating the myocardial matrix into heart failure recognition and management. Circ Res 113:725–738. doi:10.1161/CIRCRESAHA.113.300309

    Article  PubMed  CAS  Google Scholar 

  25. Turner NA (2011) Therapeutic regulation of cardiac fibroblast function: targeting stress-activated protein kinase pathways. Future Cardiol 7:673–691. doi:10.2217/fca.11.41

    Article  PubMed  CAS  Google Scholar 

  26. Turner NA, Das A, Warburton P, O’Regan DJ, Ball SG, Porter KE (2009) Interleukin-1alpha stimulates proinflammatory cytokine expression in human cardiac myofibroblasts. Am J Physiol Heart Circ Physiol 297:H1117–H1127. doi:10.1152/ajpheart.00372.2009

    Article  PubMed  CAS  Google Scholar 

  27. Udelson JE, Konstam MA (2011) Ventricular remodeling fundamental to the progression (and regression) of heart failure. J Am Coll Cardiol 57:1477–1479. doi:10.1016/j.jacc.2011.01.009

    Article  PubMed  Google Scholar 

  28. Valen G (2011) Innate immunity and remodelling. Heart Fail Rev 16:71–78. doi:10.1007/s10741-010-9187-1

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. van den Borne SW, Diez J, Blankesteijn WM, Verjans J, Hofstra L, Narula J (2010) Myocardial remodeling after infarction: the role of myofibroblasts. Nat Rev Cardiol 7:30–37. doi:10.1038/nrcardio.2009.199

    Article  PubMed  Google Scholar 

  30. Wang J, Chen H, Seth A, McCulloch CA (2003) Mechanical force regulation of myofibroblast differentiation in cardiac fibroblasts. Am J Physiol Heart Circ Physiol 285:H1871–H1881. doi:10.1152/ajpheart.00387.2003

    PubMed  CAS  Google Scholar 

  31. Wang L, Pedroja BS, Meyers EE, Garcia AL, Twining SS, Bernstein AM (2012) Degradation of internalized alphavbeta5 integrin is controlled by uPAR bound uPA: effect on beta1 integrin activity and alpha-SMA stress fiber assembly. PLoS One 7:e33915. doi:10.1371/journal.pone.0033915

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. Westermann D, Becher PM, Lindner D, Savvatis K, Xia Y, Frohlich M, Hoffmann S, Schultheiss HP, Tschope C (2012) Selective PDE5A inhibition with sildenafil rescues left ventricular dysfunction, inflammatory immune response and cardiac remodeling in angiotensin II-induced heart failure in vivo. Basic Res Cardiol 107:308. doi:10.1007/s00395-012-0308-y

    Article  PubMed  Google Scholar 

  33. Westermann D, Lindner D, Kasner M, Zietsch C, Savvatis K, Escher F, von Schlippenbach J, Skurk C, Steendijk P, Riad A, Poller W, Schultheiss HP, Tschope C (2011) Cardiac inflammation contributes to changes in the extracellular matrix in patients with heart failure and normal ejection fraction. Circ Heart Fail 4:44–52. doi:10.1161/CIRCHEARTFAILURE.109.931451

    Article  PubMed  Google Scholar 

  34. Westermann D, Rutschow S, Van Linthout S, Linderer A, Bucker-Gartner C, Sobirey M, Riad A, Pauschinger M, Schultheiss HP, Tschope C (2006) Inhibition of p38 mitogen-activated protein kinase attenuates left ventricular dysfunction by mediating pro-inflammatory cardiac cytokine levels in a mouse model of diabetes mellitus. Diabetologia 49:2507–2513. doi:10.1007/s00125-006-0385-2

    Article  PubMed  CAS  Google Scholar 

  35. Westermann D, Savvatis K, Lindner D, Zietsch C, Becher PM, Hammer E, Heimesaat MM, Bereswill S, Volker U, Escher F, Riad A, Plendl J, Klingel K, Poller W, Schultheiss HP, Tschope C (2011) Reduced degradation of the chemokine MCP-3 by matrix metalloproteinase-2 exacerbates myocardial inflammation in experimental viral cardiomyopathy. Circulation 124:2082–2093. doi:10.1161/CIRCULATIONAHA.111.035964

    Article  PubMed  CAS  Google Scholar 

  36. Westermann D, Savvatis K, Schultheiss HP, Tschope C (2010) Immunomodulation and matrix metalloproteinases in viral myocarditis. J Mol Cell Cardiol 48:468–473. doi:10.1016/j.yjmcc.2009.08.019

    Article  PubMed  CAS  Google Scholar 

  37. Zhang P, Su J, Mende U (2012) Cross talk between cardiac myocytes and fibroblasts: from multiscale investigative approaches to mechanisms and functional consequences. Am J Physiol Heart Circ Physiol 303:H1385–H1396. doi:10.1152/ajpheart.01167.2011

    Article  PubMed  CAS  PubMed Central  Google Scholar 

Download references

Acknowledgments

The present study was supported by the Deutsche Forschungsgemeinschaft (DFG, SFB-TR-19, TP A2) and by the Ernst und Berta Grimmke Stiftung. We thank Mareile Schröder, Nadine Orrin, Frauke Gotzhein, Katrin Hinz, Kerstin Puhl, and Georg Zingler for technical assistance.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Martinistr. 52, 20246, Hamburg, Germany

    Diana Lindner, Nina Fluschnik, Svenja Hinrichs, Stefan Blankenberg & Dirk Westermann

  2. Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin (CBF), Berlin, Germany

    Christin Zietsch, Juliane Tank, Wolfgang Poller, Heinz-Peter Schultheiss & Carsten Tschöpe

  3. Department of Cardiology and Pneumology/Herzzentrum, Georg-August-Universität Göttingen, Göttingen, Germany

    Samuel Sossalla

  4. DZHK (German Centre for Cardiovascular Research), Hamburg/Kiel/Luebeck, Germany

    Diana Lindner, Stefan Blankenberg & Dirk Westermann

  5. DZHK (German Centre for Cardiovascular Research), Berlin, Germany

    Heinz-Peter Schultheiss & Carsten Tschöpe

  6. DZHK (German Centre for Cardiovascular Research), Göttingen, Germany

    Samuel Sossalla

  7. Department of Internal Medicine II, University of Regensburg, Regensburg, Germany

    Lars Maier

Authors
  1. Diana Lindner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christin Zietsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Juliane Tank
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Samuel Sossalla
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nina Fluschnik
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Svenja Hinrichs
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lars Maier
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wolfgang Poller
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Stefan Blankenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Heinz-Peter Schultheiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Carsten Tschöpe
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Dirk Westermann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Diana Lindner or Dirk Westermann.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 551 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lindner, D., Zietsch, C., Tank, J. et al. Cardiac fibroblasts support cardiac inflammation in heart failure. Basic Res Cardiol 109, 428 (2014). https://doi.org/10.1007/s00395-014-0428-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00395-014-0428-7

Keywords

Search

Navigation