Skip to main content
NCBI home page
Heart logoLink to Heart
. 1996 Apr;75(4):358–362. doi: 10.1136/hrt.75.4.358

Matrix remodelling in dilated cardiomyopathy entails the occurrence of oncofetal fibronectin molecular variants.

U Gabler 1, A Berndt 1, H Kosmehl 1, U Mandel 1, L Zardi 1, S Müller 1, A Stelzner 1, D Katenkamp 1
PMCID: PMC484310  PMID: 8705761

Abstract

OBJECTIVES: To investigate whether disturbance of the cellular homoeostasis and integrity of cardiomyocytes in dilated cardiomyopathy (DCM) is accompanied by alterations in cell-matrix relations as indicated by changes in the deposition of fibronectin (FN) isoforms. DESIGN: Tissue from a case series of patients with DCM was investigated by immunohistochemistry with antibodies against FN (all variants, clone IST4), ED-A+ FN (clone IST9), ED-B+ FN (clone BC1), and oncofetal glycosylated FN (clone 5C10). The sites of de novo synthesis of FN were demonstrated by means of non-radioactive RNA in situ hybridisation (ISH) with biotinylated FN cDNA fragments as the probe. SETTING: University hospital. PATIENTS: Samples from 10 patients with clinical criteria and histological diagnosis of DCM and from 3 individuals with normal hearts. INTERVENTIONS: Samples were obtained by right ventricular endomyocardial biopsy. MAIN OUTCOME MEASURE: Distribution of oncofetal FN variants in DCM hearts. RESULTS: Immunostaining of FN (IST4, all variants) showed a coarse interstitial network in normal and diseased myocardium. ED-A+ FN was deposited as fine interstitial spots in normal myocardium and in DCM samples. Immunostaining for oncofetal glycosylated FN and ED-B+ FN was not seen in normal adult myocardium, whereas myocardium from DCM patients showed focal and delicate staining in the interstitium. RNA ISH showed that these deposits resulted from local FN synthesis. CONCLUSION: The results accord with de novo expression of oncofetal FN variants in hearts from patients with DCM. The oncofetal FN variants may serve as disease markers in myocardium affected by DCM.

Full text

PDF
358

Images in this article

359Image
on p.359
359Image
on p.359

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abelmann W. H., Lorell B. H. The challenge of cardiomyopathy. J Am Coll Cardiol. 1989 May;13(6):1219–1239. doi: 10.1016/0735-1097(89)90293-3. [DOI] [PubMed] [Google Scholar]
  2. Adams J. C., Watt F. M. Regulation of development and differentiation by the extracellular matrix. Development. 1993 Apr;117(4):1183–1198. doi: 10.1242/dev.117.4.1183. [DOI] [PubMed] [Google Scholar]
  3. Ahumada G. G., Rennard S. I., Figueroa A. A., Silver M. H. Cardiac fibronectin: developmental distribution and quantitative comparison of possible sites of synthesis. J Mol Cell Cardiol. 1981 Jul;13(7):667–678. doi: 10.1016/0022-2828(81)90274-1. [DOI] [PubMed] [Google Scholar]
  4. Arbustini E., Gavazzi A., Pozzi R., Grasso M., Pucci A., Campana C., Graziano G., Martinetti M., Cuccia M., Salvaneschi L. The morphologic spectrum of dilated cardiomyopathy and its relation to immune-response genes. Am J Cardiol. 1989 Nov 1;64(16):991–995. doi: 10.1016/0002-9149(89)90796-0. [DOI] [PubMed] [Google Scholar]
  5. Borg T. K. Development of the connective tissue network in the neonatal hamster heart. Am J Anat. 1982 Dec;165(4):435–443. doi: 10.1002/aja.1001650407. [DOI] [PubMed] [Google Scholar]
  6. Borsi L., Carnemolla B., Castellani P., Rosellini C., Vecchio D., Allemanni G., Chang S. E., Taylor-Papadimitriou J., Pande H., Zardi L. Monoclonal antibodies in the analysis of fibronectin isoforms generated by alternative splicing of mRNA precursors in normal and transformed human cells. J Cell Biol. 1987 Mar;104(3):595–600. doi: 10.1083/jcb.104.3.595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Carnemolla B., Balza E., Siri A., Zardi L., Nicotra M. R., Bigotti A., Natali P. G. A tumor-associated fibronectin isoform generated by alternative splicing of messenger RNA precursors. J Cell Biol. 1989 Mar;108(3):1139–1148. doi: 10.1083/jcb.108.3.1139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Carnemolla B., Leprini A., Allemanni G., Saginati M., Zardi L. The inclusion of the type III repeat ED-B in the fibronectin molecule generates conformational modifications that unmask a cryptic sequence. J Biol Chem. 1992 Dec 5;267(34):24689–24692. [PubMed] [Google Scholar]
  9. Carsons S., Clausen H., Wolf J. Expression of a developmentally regulated epitope on fibronectins from the synovial fluid of patients with rheumatic disease. J Rheumatol. 1994 Oct;21(10):1888–1891. [PubMed] [Google Scholar]
  10. Chiquet-Ehrismann R. Tenascin and other adhesion-modulating proteins in cancer. Semin Cancer Biol. 1993 Oct;4(5):301–310. [PubMed] [Google Scholar]
  11. David L., Mandel U., Clausen H., Sobrinho-Simões M. Immunohistochemical expression of oncofetal fibronectin in benign and malignant lesions of the stomach. Eur J Cancer. 1993;29A(14):2070–2071. doi: 10.1016/0959-8049(93)90476-v. [DOI] [PubMed] [Google Scholar]
  12. Farhadian F., Barrieux A., Lortet S., Marotte F., Oliviero P., Rappaport L., Samuel J. L. Differential splicing of fibronectin pre-messenger ribonucleic acid during cardiac ontogeny and development of hypertrophy in the rat. Lab Invest. 1994 Oct;71(4):552–559. [PubMed] [Google Scholar]
  13. Ffrench-Constant C., Hynes R. O. Alternative splicing of fibronectin is temporally and spatially regulated in the chicken embryo. Development. 1989 Jun;106(2):375–388. doi: 10.1242/dev.106.2.375. [DOI] [PubMed] [Google Scholar]
  14. Ffrench-Constant C., Van de Water L., Dvorak H. F., Hynes R. O. Reappearance of an embryonic pattern of fibronectin splicing during wound healing in the adult rat. J Cell Biol. 1989 Aug;109(2):903–914. doi: 10.1083/jcb.109.2.903. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kasper E. K., Agema W. R., Hutchins G. M., Deckers J. W., Hare J. M., Baughman K. L. The causes of dilated cardiomyopathy: a clinicopathologic review of 673 consecutive patients. J Am Coll Cardiol. 1994 Mar 1;23(3):586–590. doi: 10.1016/0735-1097(94)90740-4. [DOI] [PubMed] [Google Scholar]
  16. Kawahara E., Mukai A., Oda Y., Nakanishi I., Iwa T. Left ventriculotomy of the heart: tissue repair and localization of collagen types I, II, III, IV, V, VI and fibronectin. Virchows Arch A Pathol Anat Histopathol. 1990;417(3):229–236. doi: 10.1007/BF01600138. [DOI] [PubMed] [Google Scholar]
  17. Kornblihtt A. R., Umezawa K., Vibe-Pedersen K., Baralle F. E. Primary structure of human fibronectin: differential splicing may generate at least 10 polypeptides from a single gene. EMBO J. 1985 Jul;4(7):1755–1759. doi: 10.1002/j.1460-2075.1985.tb03847.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kornblihtt A. R., Vibe-Pedersen K., Baralle F. E. Isolation and characterization of cDNA clones for human and bovine fibronectins. Proc Natl Acad Sci U S A. 1983 Jun;80(11):3218–3222. doi: 10.1073/pnas.80.11.3218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Langbein L., Kosmehl H., Katenkamp D., Neupert G., Stiller K. J. Experimentally induced murine rhabdomyosarcomas--correlation between cellular contacts, matrix formation and cellular differentiation. Differentiation. 1990 Sep;44(3):185–196. doi: 10.1111/j.1432-0436.1990.tb00617.x. [DOI] [PubMed] [Google Scholar]
  20. Mandel U., Gaggero B., Reibel J., Therkildsen M. H., Dabelsteen E., Clausen H. Oncofetal fibronectins in oral carcinomas: correlation of two different types. APMIS. 1994 Sep;102(9):695–702. [PubMed] [Google Scholar]
  21. Mandel U., Hamilton Therkildsen M., Reibel J., Sweeney B., Matsuura H., Hakomori S., Dabelsteen E., Clausen H. Cancer-associated changes in glycosylation of fibronectin. Immunohistological localization of oncofetal fibronectin defined by monoclonal antibodies. APMIS. 1992 Sep;100(9):817–826. [PubMed] [Google Scholar]
  22. Matsuura H., Hakomori S. The oncofetal domain of fibronectin defined by monoclonal antibody FDC-6: its presence in fibronectins from fetal and tumor tissues and its absence in those from normal adult tissues and plasma. Proc Natl Acad Sci U S A. 1985 Oct;82(19):6517–6521. doi: 10.1073/pnas.82.19.6517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Matsuura H., Takio K., Titani K., Greene T., Levery S. B., Salyan M. E., Hakomori S. The oncofetal structure of human fibronectin defined by monoclonal antibody FDC-6. Unique structural requirement for the antigenic specificity provided by a glycosylhexapeptide. J Biol Chem. 1988 Mar 5;263(7):3314–3322. [PubMed] [Google Scholar]
  24. Olden K. Adhesion molecules and inhibitors of glycosylation in cancer. Semin Cancer Biol. 1993 Oct;4(5):269–276. [PubMed] [Google Scholar]
  25. Oyama F., Hirohashi S., Sakamoto M., Titani K., Sekiguchi K. Coordinate oncodevelopmental modulation of alternative splicing of fibronectin pre-messenger RNA at ED-A, ED-B, and CS1 regions in human liver tumors. Cancer Res. 1993 May 1;53(9):2005–2011. [PubMed] [Google Scholar]
  26. Oyama F., Hirohashi S., Shimosato Y., Titani K., Sekiguchi K. Oncodevelopmental regulation of the alternative splicing of fibronectin pre-messenger RNA in human lung tissues. Cancer Res. 1990 Feb 15;50(4):1075–1078. [PubMed] [Google Scholar]
  27. Parker T. G., Schneider M. D. Growth factors, proto-oncogenes, and plasticity of the cardiac phenotype. Annu Rev Physiol. 1991;53:179–200. doi: 10.1146/annurev.ph.53.030191.001143. [DOI] [PubMed] [Google Scholar]
  28. Riou J. F., Umbhauer M., Shi D. L., Boucaut J. C. Tenascin: a potential modulator of cell-extracellular matrix interactions during vertebrate embryogenesis. Biol Cell. 1992;75(1):1–9. doi: 10.1016/0248-4900(92)90118-k. [DOI] [PubMed] [Google Scholar]
  29. Roberts W. C., Siegel R. J., McManus B. M. Idiopathic dilated cardiomyopathy: analysis of 152 necropsy patients. Am J Cardiol. 1987 Dec 1;60(16):1340–1355. doi: 10.1016/0002-9149(87)90618-7. [DOI] [PubMed] [Google Scholar]
  30. Samuel J. L., Barrieux A., Dufour S., Dubus I., Contard F., Koteliansky V., Farhadian F., Marotte F., Thiéry J. P., Rappaport L. Accumulation of fetal fibronectin mRNAs during the development of rat cardiac hypertrophy induced by pressure overload. J Clin Invest. 1991 Nov;88(5):1737–1746. doi: 10.1172/JCI115492. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Schaper J., Speiser B. The extracellular matrix in the failing human heart. Basic Res Cardiol. 1992;87 (Suppl 1):303–309. doi: 10.1007/978-3-642-72474-9_26. [DOI] [PubMed] [Google Scholar]
  32. Schwarzbauer J. E. Alternative splicing of fibronectin: three variants, three functions. Bioessays. 1991 Oct;13(10):527–533. doi: 10.1002/bies.950131006. [DOI] [PubMed] [Google Scholar]
  33. Shekhonin B. V., Domogatsky S. P., Idelson G. L., Koteliansky V. E. Participance of fibronectin and various collagen types in the formation of fibrous extracellular matrix in cardiosclerosis. J Mol Cell Cardiol. 1988 Jun;20(6):501–508. doi: 10.1016/s0022-2828(88)80077-4. [DOI] [PubMed] [Google Scholar]
  34. Speiser B., Weihrauch D., Riess C. F., Schaper J. The extracellular matrix in human cardiac tissue. Part II: Vimentin, laminin, and fibronectin. Cardioscience. 1992 Mar;3(1):41–49. [PubMed] [Google Scholar]
  35. Tazelaar H. D., Gay R. E., Rowan R. A., Billingham M. E., Gay S. Collagen profile in the transplanted heart. Hum Pathol. 1990 Apr;21(4):424–428. doi: 10.1016/0046-8177(90)90205-j. [DOI] [PubMed] [Google Scholar]
  36. Vartio T., Laitinen L., Närvänen O., Cutolo M., Thornell L. E., Zardi L., Virtanen I. Differential expression of the ED sequence-containing form of cellular fibronectin in embryonic and adult human tissues. J Cell Sci. 1987 Nov;88(Pt 4):419–430. doi: 10.1242/jcs.88.4.419. [DOI] [PubMed] [Google Scholar]
  37. Vogel W., Kosmehl H., Katenkamp D., Langbein L. Differentiation dependent matrix formation (fibronectin and laminin) in an experimental murine rhabdomyosarcoma model. Acta Histochem. 1991;90(2):181–188. doi: 10.1016/S0065-1281(11)80058-9. [DOI] [PubMed] [Google Scholar]
  38. Weber K. T., Pick R., Silver M. A., Moe G. W., Janicki J. S., Zucker I. H., Armstrong P. W. Fibrillar collagen and remodeling of dilated canine left ventricle. Circulation. 1990 Oct;82(4):1387–1401. doi: 10.1161/01.cir.82.4.1387. [DOI] [PubMed] [Google Scholar]
  39. Zardi L., Carnemolla B., Siri A., Petersen T. E., Paolella G., Sebastio G., Baralle F. E. Transformed human cells produce a new fibronectin isoform by preferential alternative splicing of a previously unobserved exon. EMBO J. 1987 Aug;6(8):2337–2342. doi: 10.1002/j.1460-2075.1987.tb02509.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. von der Mark K., Ocalan M. Antagonistic effects of laminin and fibronectin on the expression of the myogenic phenotype. Differentiation. 1989 May;40(2):150–157. doi: 10.1111/j.1432-0436.1989.tb00823.x. [DOI] [PubMed] [Google Scholar]

Articles from Heart are provided here courtesy of BMJ Publishing Group

RESOURCES