Skip to main content

Advertisement

SpringerLink
Log in

Transcriptional and posttranscriptional regulators of biglycan in cardiac fibroblasts

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

Abstract

Biglycan, a small leucine-rich proteoglycan, is essential for scar formation and preservation of hemodynamic function after myocardial infarction, as shown in biglycan-knockout mice. Because of this important role in cardiac pathophysiology, we aimed to identify regulators of biglycan expression and posttranslational modifications in cardiac fibroblasts. Cardiac fibroblasts were isolated from neonatal Wistar-Kyoto rats and used in the first passage. Expression of biglycan was analyzed after metabolic labeling with [35S]-sulfate by SDS-polyacrylamide gel electrophoresis and molecular sieve chromatography; mRNA expression was examined by Northern analysis and real-time RT-PCR. Serum, thrombin, transforming growth factor β1 (TGFβ 1) and platelet-derived growth factor BB (PDGF-BB) strongly increased [35S]-labeled proteoglycan levels. Tumor necrosis factor alpha further increased the stimulatory effect of PDGF-BB. PDGF-BB increased glycosaminoglycan (GAG) chain length as shown by molecular sieve chromatography after β-elimination to release GAG chains. Nitric oxide was the only negative regulator of biglycan as evidenced by marked downregulation in response to DETA-NO ((Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate), a long acting nitric oxide donor and SNAP (S-nitroso-N-acetyl-l,l-penicillamine), which completely inhibited PDGF-BB-induced secretion of total [35S]-labeled proteoglycans and biglycan mRNA expression. Of note, the molecular weight of biglycan GAG chains was even further increased by NO donors compared to control and PDGF-BB stimulation. The current results suggest that in cardiac fibroblasts, biglycan is induced by a variety of stimuli including serum, thrombin and growth factors such as PDGF-BB and TGFβ1. This response is counteracted by NO and enhanced by TNFα. Interestingly, both up- and downregulation were associated with posttranslational increase of GAG chain length.

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

Similar content being viewed by others

References

  1. Ahmed MS, Oie E, Vinge LE, Yndestad A, Andersen GG, Andersson Y, Attramadal T, Attramadal H (2003) Induction of myocardial biglycan in heart failure in rats—an extracellular matrix component targeted by AT(1) receptor antagonism. Cardiovasc Res 60:557–568

    Article  CAS  PubMed  Google Scholar 

  2. Ameye L, Aria D, Jepsen K, Oldberg A, Xu T, Young MF (2002) Abnormal collagen fibrils in tendons of biglycan/fibromodulin-deficient mice lead to gait impairment, ectopic ossification, and osteoarthritis. Faseb J 16:673–680

    Article  CAS  PubMed  Google Scholar 

  3. Ameye L, Young MF (2002) Mice deficient in small leucine-rich proteoglycans: novel in vivo models for osteoporosis, osteoarthritis, Ehlers-Danlos syndrome, muscular dystrophy, and corneal diseases. Glycobiology 12:107R–116R

    Article  CAS  PubMed  Google Scholar 

  4. Caulfield JB, Borg TK (1979) The collagen network of the heart. Lab Invest 40:364–372

    CAS  PubMed  Google Scholar 

  5. Chang MY, Potter-Perigo S, Tsoi C, Chait A, Wight TN (2000) Oxidized low density lipoproteins regulate synthesis of monkey aortic smooth muscle cell proteoglycans that have enhanced native low density lipoprotein binding properties. J Biol Chem 275:4766–4773

    Article  CAS  PubMed  Google Scholar 

  6. Corsi A, Xu T, Chen XD, Boyde A, Liang J, Mankani M, Sommer B, Iozzo RV, Eichstetter I, Robey PG, Bianco P, Young MF (2002) Phenotypic effects of biglycan deficiency are linked to collagen fibril abnormalities, are synergized by decorin deficiency, and mimic Ehlers-Danlos-like changes in bone and other connective tissues. J Bone Miner Res 17:1180–1189

    Article  CAS  PubMed  Google Scholar 

  7. Dai G, Freudenberger T, Zipper P, Melchior A, Grether-Beck S, Rabausch B, de Groot J, Twarock S, Hanenberg H, Homey B, Krutmann J, Reifenberger J, Fischer JW (2007) Chronic ultraviolet B irradiation causes loss of hyaluronic acid from mouse dermis because of down-regulation of hyaluronic acid synthases. Am J Pathol 171:1451–1461

    Article  CAS  PubMed  Google Scholar 

  8. Danielson KG, Baribault H, Holmes DF, Graham H, Kadler KE, Iozzo RV (1997) Targeted disruption of decorin leads to abnormal collagen fibril morphology and skin fragility. J Cell Biol 136:729–743

    Article  CAS  PubMed  Google Scholar 

  9. De Luca A, Santra M, Baldi A, Giordano A, Iozzo RV (1996) Decorin-induced growth suppression is associated with up-regulation of p21, an inhibitor of cyclin-dependent kinases. J Biol Chem 271:18961–18965

    Article  PubMed  Google Scholar 

  10. Doi M, Kusachi S, Murakami T, Ninomiya Y, Murakami M, Nakahama M, Takeda K, Komatsubara I, Naito I, Tsuji T (2000) Time-dependent changes of decorin in the infarct zone after experimentally induced myocardial infarction in rats: comparison with biglycan. Pathol Res Pract 196:23–33

    CAS  PubMed  Google Scholar 

  11. Eghbali M, Blumenfeld OO, Seifter S, Buttrick PM, Leinwand LA, Robinson TF, Zern MA, Giambrone MA (1989) Localization of types I, III and IV collagen mRNAs in rat heart cells by in situ hybridization. J Mol Cell Cardiol 21:103–113

    Article  CAS  PubMed  Google Scholar 

  12. Eghbali M, Czaja MJ, Zeydel M, Weiner FR, Zern MA, Seifter S, Blumenfeld OO (1988) Collagen chain mRNAs in isolated heart cells from young and adult rats. J Mol Cell Cardiol 20:267–276

    Article  CAS  PubMed  Google Scholar 

  13. Fischer JW, Kinsella MG, Levkau B, Clowes AW, Wight TN (2001) Retroviral overexpression of decorin differentially affects the response of arterial smooth muscle cells to growth factors. Arterioscler Thromb Vasc Biol 21:777–784

    CAS  PubMed  Google Scholar 

  14. Frantz S, Hu K, Adamek A, Wolf J, Sallam A, Maier SK, Lonning S, Ling H, Ertl G, Bauersachs J (2008) Transforming growth factor beta inhibition increases mortality and left ventricular dilatation after myocardial infarction. Basic Res Cardiol 103:485–492

    Article  CAS  PubMed  Google Scholar 

  15. Geng Y, McQuillan D, Roughley PJ (2006) SLRP interaction can protect collagen fibrils from cleavage by collagenases. Matrix Biol 25:484–491

    Article  CAS  PubMed  Google Scholar 

  16. Grande-Allen KJ, Calabro A, Gupta V, Wight TN, Hascall VC, Vesely I (2004) Glycosaminoglycans and proteoglycans in normal mitral valve leaflets and chordae: association with regions of tensile and compressive loading. Glycobiology 14:621–633

    Article  CAS  PubMed  Google Scholar 

  17. Heegaard AM, Corsi A, Danielsen CC, Nielsen KL, Jorgensen HL, Riminucci M, Young MF, Bianco P (2007) Biglycan deficiency causes spontaneous aortic dissection and rupture in mice. Circulation 115:2731–2738

    Article  CAS  PubMed  Google Scholar 

  18. Hoch RV, Soriano P (2003) Roles of PDGF in animal development. Development 130:4769–4784

    Article  CAS  PubMed  Google Scholar 

  19. Hsieh PC, Davis ME, Gannon J, Macgillivray C, Lee RT (2006) Controlled delivery of PDGF-BB for myocardial protection using injectable self-assembling peptide nanofibers. J Clin Invest 116:237–248

    Article  CAS  PubMed  Google Scholar 

  20. Hwang TL, Wu CC, Teng CM (1998) Comparison of two soluble guanylyl cyclase inhibitors, methylene blue and ODQ, on sodium nitroprusside-induced relaxation in guinea pig trachea. Br J Pharmacol 125:1158–1163

    Article  CAS  PubMed  Google Scholar 

  21. Ignarro LJ, Buga GM, Wei LH, Bauer PM, Wu G, del Soldato P (2001) Role of the arginine–nitric oxide pathway in the regulation of vascular smooth muscle cell proliferation. Proc Natl Acad Sci USA 98:4202–4208

    Article  CAS  PubMed  Google Scholar 

  22. Jugdutt BI (2003) Ventricular remodeling after infarction and the extracellular collagen matrix: when is enough enough? Circulation 108:1395–1403

    Article  PubMed  Google Scholar 

  23. Kalra DK, Zhu X, Ramchandani MK, Lawrie G, Reardon MJ, Lee-Jackson D, Winters WL, Sivasubramanian N, Mann DL, Zoghbi WA (2002) Increased myocardial gene expression of tumor necrosis factor-alpha and nitric oxide synthase-2: a potential mechanism for depressed myocardial function in hibernating myocardium in humans. Circulation 105:1537–1540

    Article  CAS  PubMed  Google Scholar 

  24. Keefer LK, Nims RW, Davies KM, Wink DA (1996) “NONOates” (1-substituted diazen-1-ium-1, 2-diolates) as nitric oxide donors: convenient nitric oxide dosage forms. Methods Enzymol 268:281–293

    Article  CAS  PubMed  Google Scholar 

  25. Kim NN, Villegas S, Summerour SR, Villarreal FJ (1999) Regulation of cardiac fibroblast extracellular matrix production by bradykinin and nitric oxide. J Mol Cell Cardiol 31:457–466

    Article  CAS  PubMed  Google Scholar 

  26. Kinsella MG, Fischer JW, Mason DP, Wight TN (2000) Retrovirally mediated expression of decorin by macrovascular endothelial cells. Effects on cellular migration and fibronectin fibrillogenesis in vitro. J Biol Chem 275:13924–13932

    Article  CAS  PubMed  Google Scholar 

  27. Kolpakov V, Gordon D, Kulik TJ (1995) Nitric oxide-generating compounds inhibit total protein and collagen synthesis in cultured vascular smooth muscle cells. Circ Res 76:305–309

    CAS  PubMed  Google Scholar 

  28. Liu J, Fitzli D, Liu M, Tseu I, Caniggia I, Rotin D, Post M (1998) PDGF-induced glycosaminoglycan synthesis is mediated via phosphatidylinositol 3-kinase. Am J Physiol 274:L702–L713

    CAS  PubMed  Google Scholar 

  29. Mann DL (2002) Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circ Res 91:988–998

    Article  CAS  PubMed  Google Scholar 

  30. Margolis RK, Goossen B, Tekotte H, Hilgenberg L, Margolis RU (1991) Effects of beta-xylosides on proteoglycan biosynthesis and morphology of PC12 pheochromocytoma cells and primary cultures of rat cerebellum. J Cell Sci 99:237–246

    CAS  PubMed  Google Scholar 

  31. Nakashima Y, Fujii H, Sumiyoshi S, Wight TN, Sueishi K (2007) Early human atherosclerosis: accumulation of lipid and proteoglycans in intimal thickenings followed by macrophage infiltration. Arterioscler Thromb Vasc Biol 27:1159–1165

    Article  CAS  PubMed  Google Scholar 

  32. Pfeffer MA, Braunwald E (1990) Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation 81:1161–1172

    CAS  PubMed  Google Scholar 

  33. Rannou F, Richette P, Benallaoua M, Francois M, Genries V, Korwin-Zmijowska C, Revel M, Corvol M, Poiraudeau S (2003) Cyclic tensile stretch modulates proteoglycan production by intervertebral disc annulus fibrosus cells through production of nitrite oxide. J Cell Biochem 90:148–157

    Article  CAS  PubMed  Google Scholar 

  34. Rizvi MA, Myers PR (1997) Nitric oxide modulates basal and endothelin-induced coronary artery vascular smooth muscle cell proliferation and collagen levels. J Mol Cell Cardiol 29:1779–1789

    Article  CAS  PubMed  Google Scholar 

  35. Rosado A, Lamas GA (1997) Left ventricular remodeling: clinical significance and therapy. Basic Res Cardiol 92:66–68

    CAS  PubMed  Google Scholar 

  36. 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  CAS  PubMed  Google Scholar 

  37. Sam F, Xie Z, Ooi H, Kerstetter DL, Colucci WS, Singh M, Singh K (2004) Mice lacking osteopontin exhibit increased left ventricular dilation and reduced fibrosis after aldosterone infusion. Am J Hypertens 17:188–193

    Article  CAS  PubMed  Google Scholar 

  38. Schaefer L, Beck KF, Raslik I, Walpen S, Mihalik D, Micegova M, Macakova K, Schonherr E, Seidler DG, Varga G, Schaefer RM, Kresse H, Pfeilschifter J (2003) Biglycan, a nitric oxide-regulated gene, affects adhesion, growth, and survival of mesangial cells. J Biol Chem 278:26227–26237

    Article  CAS  PubMed  Google Scholar 

  39. Schönherr E, Järveläinen HT, Kinsella MG, Sandell LJ, Wight TN (1993) Platelet-derived growth factor and transforming growth factor-b1 differentially affect the synthesis of biglycan and decorin by monkey arterial smooth muscle cells. Arterioscler Thromb 13:1026–1036

    PubMed  Google Scholar 

  40. Schönherr E, Kinsella MG, Wight TN (1997) Genistein selectively inhibits platelet-derived growth factor stimulated versican biosynthesis in monkey arterial smooth muscle cells. Arch Biochem Biophys 339:353–361

    Article  PubMed  Google Scholar 

  41. Schulz R, Heusch G (2009) Tumor necrosis factor-alpha and its receptors 1 and 2: yin and yang in myocardial infarction? Circulation 119:1355–1357

    Article  PubMed  Google Scholar 

  42. Scott PG, Nakano T, Dodd CM, Pringle GA, Kuc IM (1989) Proteoglycans of the articular disc of the bovine temporomandibular joint. II. Low molecular weight dermatan sulphate proteoglycan. Matrix 9:284–292

    CAS  PubMed  Google Scholar 

  43. Sen A, Miller JC, Reynolds R, Willerson JT, Buja LM, Chien KR (1988) Inhibition of the release of arachidonic acid prevents the development of sarcolemmal membrane defects in cultured rat myocardial cells during adenosine triphosphate depletion. J Clin Invest 82:1333–1338

    Article  CAS  PubMed  Google Scholar 

  44. Shihab FS, Yi H, Bennett WM, Andoh TF (2000) Effect of nitric oxide modulation on TGF-beta1 and matrix proteins in chronic cyclosporine nephrotoxicity. Kidney Int 58:1174–1185

    Article  CAS  PubMed  Google Scholar 

  45. Sun Y, Weber KT (2000) Infarct scar: a dynamic tissue. Cardiovasc Res 46:250–256

    Article  CAS  PubMed  Google Scholar 

  46. Theocharis AD, Karamanos NK (2002) Decreased biglycan expression and differential decorin localization in human abdominal aortic aneurysms. Atherosclerosis 165:221–230

    Article  CAS  PubMed  Google Scholar 

  47. Tiede K, Stoter K, Petrik C, Chen WB, Ungefroren H, Kruse ML, Stoll M, Unger T, Fischer JW (2003) Angiotensin II AT(1)-receptor induces biglycan in neonatal cardiac fibroblasts via autocrine release of TGFbeta in vitro. Cardiovasc Res 60:538–546

    Article  CAS  PubMed  Google Scholar 

  48. Tollefsen DM (2007) Heparin cofactor II modulates the response to vascular injury. Arterioscler Thromb Vasc Biol 27:454–460

    Article  CAS  PubMed  Google Scholar 

  49. van den Boom M, Sarbia M, von Wnuck Lipinski K, Mann P, Meyer-Kirchrath J, Rauch BH, Grabitz K, Levkau B, Schror K, Fischer JW (2006) Differential regulation of hyaluronic acid synthase isoforms in human saphenous vein smooth muscle cells: possible implications for vein graft stenosis. Circ Res 98:36–44

    Article  PubMed  Google Scholar 

  50. 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

    Article  PubMed  Google Scholar 

  51. Wang D, Yang XP, Liu YH, Carretero OA, LaPointe MC (1999) Reduction of myocardial infarct size by inhibition of inducible nitric oxide synthase. Am J Hypertens 12:174–182

    Article  CAS  PubMed  Google Scholar 

  52. Wasteson Å, Uthne K, Westermark B (1973) A novel assay for the biosynthesis of sulfated polysaccharide and its application to studies on the effects of somatomedin on cultured cells. Biochem J 136:1069–1074

    CAS  PubMed  Google Scholar 

  53. Weber KT (1997) Extracellular matrix remodeling in heart failure: a role for de novo angiotensin II generation. Circulation 96:4065–4082

    CAS  PubMed  Google Scholar 

  54. Westermann D, Mersmann J, Melchior A, Freudenberger T, Petrik C, Schaefer L, Lullmann-Rauch R, Lettau O, Jacoby C, Schrader J, Brand-Herrman SM, Young MF, Schultheiss HP, Levkau B, Baba HA, Unger T, Zacharowski K, Tschope C, Fischer JW (2008) Biglycan is required for adaptive remodeling after myocardial infarction. Circulation 117:1269–1276

    Article  CAS  PubMed  Google Scholar 

  55. 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  CAS  PubMed  Google Scholar 

  56. Whittaker P (1997) Collagen and ventricular remodeling after acute myocardial infarction: concepts and hypotheses. Basic Res Cardiol 92:79–81

    CAS  PubMed  Google Scholar 

  57. Wildhirt SM, Dudek RR, Suzuki H, Pinto V, Narayan KS, Bing RJ (1995) Immunohistochemistry in the identification of nitric oxide synthase isoenzymes in myocardial infarction. Cardiovasc Res 29:526–531

    CAS  PubMed  Google Scholar 

  58. Wu CC, Ko FN, Kuo SC, Lee FY, Teng CM (1995) YC-1 inhibited human platelet aggregation through NO independent activation of soluble guanylate cyclase. Br J Pharmacol 116:1973–1978

    CAS  PubMed  Google Scholar 

  59. Xu T, Bianco P, Fisher LW, Longenecker G, Smith E, Goldstein S, Bonadio J, Boskey A, Heegaard AM, Sommer B, Satomura K, Dominguez P, Zhao C, Kulkarni AB, Robey PG, Young MF (1998) Targeted disruption of the biglycan gene leads to an osteoporosis-like phenotype in mice. Nat Genet 20:78–82

    Article  CAS  PubMed  Google Scholar 

  60. Yamaguchi Y, Mann DM, Ruoslahti E (1990) Negative regulation of transforming growth factor-beta by the proteoglycan decorin. Nature 346:281–284

    Article  CAS  PubMed  Google Scholar 

  61. Yamamoto K, Kusachi S, Ninomiya Y, Murakami M, Doi M, Takeda K, Shinji T, Higashi T, Koide N, Tsuji T (1998) Increase in the expression of biglycan mRNA expression co-localized closely with that of type I collagen mRNA in the infarct zone after experimentally-induced myocardial infarction in rats. J Mol Cell Cardiol 30:1749–1756

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

A.M.-B. was supported by the Deutsche Forschungsgemeinschaft, GRK 1089.

Author information

Authors and Affiliations

  1. Institut für Pharmakologie, Universitätsklinikum Essen, Universität Duisburg-Essen, Hufelandstrasse 55, 45147, Essen, Germany

    Karen Tiede, Ariane Melchior-Becker & Jens W. Fischer

Authors
  1. Karen Tiede
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ariane Melchior-Becker
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jens W. Fischer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jens W. Fischer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tiede, K., Melchior-Becker, A. & Fischer, J.W. Transcriptional and posttranscriptional regulators of biglycan in cardiac fibroblasts. Basic Res Cardiol 105, 99–108 (2010). https://doi.org/10.1007/s00395-009-0049-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00395-009-0049-8

Keywords

Search

Navigation