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Carboxyamido-triazol (CAI) inhibiert Unterschritte der choroidalen Neovaskularisation an choroidalen Endothelzellen und retinalen Pigmentepithelzellen in vitro

Carboxyamido-triazole inhibits substeps of choroidal neovascularization on retinal pigment epithelial cells and choroidal endothelial cells in vitro

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Zusammenfassung

Ziel:

Retinale Pigmentepithelzellen (RPEs) und choroidale Endothelzellen (CECs) spielen eine wichtige Rolle bei der Ausbildung einer choroidalen Neovaskularisation im Rahmen der altersbedingten exsudativen Makuladegeneration (AMD). In dieser Studie untersuchen wir den Einfluss der die Kalziumsignaltransduktion modulierenden Substanz Carboxyamido-triazole (CAI) auf die Proliferation und Migration dieser Zellarten.

Methoden:

Humane fetale RPE-Zellen und bovine CECs wurden mit CAI in einem Konzentrationsbereich von 0,1–10 µM inkubiert. Die Effekte des CAI auf Serum- sowie „basic fibroblast growth factor“- (bFGF) (10 ng/ml) stimulierte Proliferation dieser Zellarten wurden bestimmt. Zusätzlich wurde der Einfluss des CAI auf die Zellmigration von CECs und RPE-Zellen untersucht.

Ergebnisse:

CAI inhibiert die Proliferation von Serum-stimulierten CECs stärker als die RPE-Zellproliferation in einer Konzentration von 10 µM. Noch ausgeprägter inhibiert CAI die bFGF-stimulierte RPE-Zell- und CEC-Proliferation. Auch die fibronektininduzierte RPE-Zell- und CEC-Migration konnte durch CAI inhibiert werden, wobei die Migration von RPE-Zellen stärker gehemmt wurde als die Migration von CECs.

Schlussfolgerung:

CAI inhibiert wichtige Subschritte der choroidalen Neovaskularisation wie Proliferation und Migration von RPE-Zellen und CECs. CAI könnte somit von Bedeutung sein für die Hemmung der choroidalen Neovaskularisation bei der exsudativen Makuladegeneration.

Abstract

Background

Retinal pigment epithelial cells (RPE cells) and choroidal endothelial cells (CECs) are important cell types in the process of choroidal neovascularization in exudative age-related macular degeneration (AMD). In this study, we evaluated the antiproliferative and antimigratory abilities of carboxyamido-triazole (CAI), a drug modulating calcium-dependent signal transduction on RPE cells and CECs.

Methods

Human fetal RPE cells and bovine CECs were exposed to CAI in a concentration range of 0.1 to 10 µM. Cell proliferation was stimulated with 10% serum or 10 ng/ml bFGF. The effect of CAIs on cell proliferation was estimated. Furthermore, we evaluated CAI’s effects on CEC and RPE cell migration induced by fibronectin.

Results

CAI had a stronger inhibitory effect on serum-induced CEC proliferation than on RPE cell proliferation. A much stronger effect was seen on the proliferation of bFGF-stimulated RPE cells and CECs. Furthermore, the fibronectin-stimulated migration of RPE cells and CECs was inhibited by CAI. In this assay, a stronger inhibitory effect was seen on RPE cells than on CECs.

Conclusion

CAI inhibits important substeps of choroidal neovascularization on RPR cells and CECs. Therefore, CAI may be of value for the treatment of choroidal neovascularization in exudative AMD.

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Literatur

  1. Asaga H, Yamada M, Senshu T (1998) Selective deimination of vimentin in calcium ionophore-induced apoptosis of mouse peritoneal macrophages. Biochem Biophys Res Commun 243:641–646

    Article  CAS  PubMed  Google Scholar 

  2. Campochiaro PA, Jerdan JA, Glaser BM (1984) Serum contains chemoattractants for human retinal pigment epithelial cells. Arch Ophthalmol 102:1830–1833

    CAS  PubMed  Google Scholar 

  3. Campochiaro PA, Soloway P, Ryan SJ, Miller JW (1999) The pathogenesis of choroidal neovascularization in patients with age-related macular degeneration. Mol Vis 5:34

    CAS  PubMed  Google Scholar 

  4. Frank RN (1997) Growth factors in age-related macular degeneration: pathogenic and therapeutic implications. Ophthalmic Res 29:341–353

    CAS  PubMed  Google Scholar 

  5. Ge S, Rempel SA, Divine G, Mikkelsen T (2000) Carboxyamido-triazole induces apoptosis in bovine aortic endothelial and human glioma cells. Clin Cancer Res 6:1248–1254

    CAS  PubMed  Google Scholar 

  6. Gommerman JL, Berger SA (1998) Protection from apoptosis by steel factor but not interleukin-3 is reversed through blockade of calcium influx. Blood 91:1891–1900

    CAS  PubMed  Google Scholar 

  7. Hoffman S, Gopalakrishna R, Gundimeda U et al. (1998) Verapamil inhibits proliferation, migration and protein kinase C activity in human retinal pigment epithelial cells. Exp Eye Res 67:45–52

    Article  CAS  PubMed  Google Scholar 

  8. Hoffmann S, Spee C, Murata T et al. (1998) Rapid isolation of choriocapillary endothelial cells by Lycopersicon esculentum-coated Dynabeads. Graefes Arch Clin Exp Ophthalmol 236:779–784

    CAS  PubMed  Google Scholar 

  9. Kirchhof B, Kirchhof E, Ryan SJ, Sorgente N (1989) Vitreous modulation of migration and proliferation of retinal pigment epithelial cells in vitro. Invest Ophthalmol Vis Sci 30:1951–1957

    PubMed  Google Scholar 

  10. Kohn EC, Alessandro R, Spoonster J et al. (1995) Angiogenesis: role of calcium-mediated signal transduction. Proc Natl Acad Sci USA 92:1307–1311

    CAS  PubMed  Google Scholar 

  11. Kohn EC, Jacobs W, Kim YS et al. (1994) Calcium influx modulates expression of matrix metalloproteinase-2 (72-kDa type IV collagenase, gelatinase A). J Biol Chem 269:21505–21511

    CAS  PubMed  Google Scholar 

  12. Kohn EC, Reed E, Sarosy G et al. (1996) Clinical investigation of a cytostatic calcium influx inhibitor in patients with refractory cancers. Cancer Res 56:569–573

    CAS  PubMed  Google Scholar 

  13. Kuriyama S, Ohuchi T, Yoshimura N, Honda Y (1991) Growth factor-induced cytosolic calcium ion transients in cultured human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 32:2882–2890

    CAS  PubMed  Google Scholar 

  14. Liotta LA, Stracke ML, Aznavoorian SA et al. (1991) Tumor cell motility. Semin Cancer Biol 2:111–114

    CAS  PubMed  Google Scholar 

  15. Masiero L, Lapidos KA, Ambudkar I, Kohn EC (1999) Regulation of the RhoA pathway in human endothelial cell spreading on type IV collagen: role of calcium influx. J Cell Sci 112 (Pt 19):3205–3213

    CAS  PubMed  Google Scholar 

  16. Presta M, Maier JA, Ragnotti G (1989) The mitogenic signaling pathway but not the plasminogen activator-inducing pathway of basic fibroblast growth factor is mediated through protein kinase C in fetal bovine aortic endothelial cells. J Cell Biol 109:1877–1884

    CAS  PubMed  Google Scholar 

  17. Presta M, Maier JA, Rusnati M, Ragnotti G (1989) Basic fibroblast growth factor: production, mitogenic response, and post-receptor signal transduction in cultured normal and transformed fetal bovine aortic endothelial cells. J Cell Physiol 141:517–526

    CAS  PubMed  Google Scholar 

  18. Sakamoto T, Sakamoto H, Hinton DR et al. (1995) In vitro studies of human choroidal endothelial cells. Curr Eye Res 14:621–627

    CAS  PubMed  Google Scholar 

  19. Takahashi K, Itagaki T, Yamagishi K et al. (1990) The role of retinal pigment epithelium in the early stage of development of subretinal neovascularization. Nippon Ganka Gakkai Zasshi 94:3–17

    CAS  PubMed  Google Scholar 

  20. Uyama M (1991) Choroidal neovascularization, experimental and clinical study. Nippon Ganka Gakkai Zasshi 95:1145–1180

    CAS  PubMed  Google Scholar 

  21. Volpe DA, Cole K, Sandeen MA, Kohn EC (1995) In vitro and in vivo myelotoxicity of CAI to human and murine hematopoietic progenitor cells. Am J Hematol 50:277–282

    CAS  PubMed  Google Scholar 

  22. Walker PR, Sikorska M (1994) Endonuclease activities, chromatin structure, and DNA degradation in apoptosis. Biochem Cell Biol 72:615–623

    CAS  PubMed  Google Scholar 

  23. Zang C, Liu H, Ries C et al. (2000) Enhanced migration of the acute promyelocytic leukemia cell line NB4 under in vitro conditions during short-term all-trans-retinoic acid treatment. J Cancer Res Clin Oncol 126:33–40

    Google Scholar 

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Authors and Affiliations

  1. Universitätsaugenklinik Leipzig, Leipzig

    S. Hoffmann & P. Wiedemann

  2. Doheny Eye Institute, University of Southern California, USC

    S. He

  3. Universitätsaugenklinik Leipzig, Liebigstraße 10–14, 04103 , Leipzig

    S. Hoffmann

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  1. S. Hoffmann
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  2. S. He
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  3. P. Wiedemann
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Correspondence to S. Hoffmann.

Additional information

Unterstützung dieser Arbeit durch die Deutsche Forschungsgemeinschaft (DFG)(WI 880\9-1) und einem Junior-Antrag der Universität Leipzig (Nr. 78311106).

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Hoffmann, S., He, S. & Wiedemann, P. Carboxyamido-triazol (CAI) inhibiert Unterschritte der choroidalen Neovaskularisation an choroidalen Endothelzellen und retinalen Pigmentepithelzellen in vitro. Ophthalmologe 101, 993–997 (2004). https://doi.org/10.1007/s00347-003-0874-3

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  • DOI: https://doi.org/10.1007/s00347-003-0874-3

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