Advertisement

Molecular Medicine

, Volume 8, Issue 9, pp 546–550 | Cite as

Beraprost Sodium, a Prostaglandin I2 Analogue, Protects Against Advanced Glycation End Products-induced Injury in Cultured Retinal Pericytes

  • Sho-ichi Yamagishi
  • Shinjiro Amano
  • Yosuke Inagaki
  • Tamami Okamoto
  • Masayoshi Takeuchi
  • Zenji Makita
Original Articles

Abstract

Background

Beraprost sodium, a prostaglandin I2 analogue, has been recently reported to exhibit beneficial effects on atherosclerosis in patients with diabetes. However, effects of beraprost sodium on microvascular injury in diabetes remain to be elucidated. We have previously shown that advanced glycation end products (AGE), senescent macroproteins formed at an accelerated rate in diabetes, caused pericyte apoptosis, thus being involved in the pathogenesis of the early phase of diabetic retinopathy. In this study, we examined whether beraprost sodium can protect against AGE-induced cytotoxicity in cultured retinal pericytes.

Materials and Methods

Intracellular formation of reactive oxygen species (ROS) was detected using a fluorescent probe. DNA synthesis was determined by measuring [3H]thymidine incorporation into cells. Apoptosis was determined by DNA fragmentations, which were quantitatively measured in an enzyme-linked immunosorbent assay.

Results

Beraprost sodium or forskolin, a stimulator of adenylate cyclase, was found to significantly inhibit AGE-induced ROS generation and the subsequent decrease in DNA synthesis in pericytes. Both treatments significantly prevented AGE-induced apoptotic cell death in pericytes. Furthermore, beraprost sodium was found to down-regulate AGE receptor mRNA levels in pericytes.

Results

The results demonstrated that cyclic AMP-elevating agents such as beraprost sodium and forskolin protected retinal pericytes from AGE-induced cytotoxicity through its anti-oxidative properties. Our present study suggests that beraprost sodium may have therapeutic potentials in treatment of patients with early diabetic retinopathy.

Notes

Acknowledgments

This work was supported in part by Grants (S.Y.) from Venture Research and Development Centers from the Ministry of Education, Culture, Sports, Science and Technology, Japan, the Suzuken Memorial Foundation, Japan and the Mochida Memorial Foundation for Medical and Pharmaceutical Research, Japan.

References

  1. 1.
    Kato R, Uji Y, Matsumoto K. (1989) Phase I study of beraprost sodium (TRK-100), an epoprostenol derivative: repeated oral administration for 10 days. Jpn. J. Clin. Pharmacol. Ther. 20: 529–539.CrossRefGoogle Scholar
  2. 2.
    Lievre M, Morand S, Besse B, et al. (2000) Oral beraprost sodium, a prostaglandin I2 analogue, for intermittent claudication. Circulation 102: 426–431.CrossRefPubMedGoogle Scholar
  3. 3.
    Isogaya M, Yamada N, Koike H, et al. (1995) Inhibition of restenosis by beraprost sodium (a prostaglandin I2 analogue) in the atherosclerotic rabbit artery after angioplasty. J. Cardiovasc. Pharmacol. 25: 947–952.CrossRefPubMedGoogle Scholar
  4. 4.
    Toyota T, Oikawa S, Beraprost Sodium Study Group. (2002) Effects of beraprost sodium (Dorner) in patients with diabetes mellitus complicated by chronic arterial obstruction. Angiology 53: 7–13.CrossRefPubMedGoogle Scholar
  5. 5.
    LíEsperance FA, James WA, Judson PH. (1990) The eye and diabetes mellitus. In: Ellenberg and Rifkinís Diabetes Mellitus, Theory and Practice, ed. Lifkin H, Porte D, Elsevier, New York, NY, pp. 661–683.Google Scholar
  6. 6.
    Mandarino LJ. (1992) Current hypotheses for the biochemical basis of diabetic retinopathy. Diabetes Care 15: 1892–1901.CrossRefPubMedGoogle Scholar
  7. 7.
    Frank RN. (1991) On the pathogenesis of diabetic retinopathy. A 1990 updata. Ophthalmology 98: 586–593.CrossRefPubMedGoogle Scholar
  8. 8.
    Yamagishi S, Hsu CC, Taniguchi M, et al. (1995) Receptor-mediated toxicity to pericytes of advanced glycosylation end products: a possible mechanism of pericyte loss in diabetic microangiopathy. Biochem. Biophys. Res. Commun. 213: 681–687.CrossRefPubMedGoogle Scholar
  9. 9.
    Yamagishi S, Amano S, Inagaki Y, et al. (2002) Advanced glycation end products-induced apoptosis and overexpression of vascular endothelial growth factor in bovine retinal pericytes. Biochem. Biophys. Res. Commun. 290: 973–978.CrossRefPubMedGoogle Scholar
  10. 10.
    Takeuchi M, Yanase Y, Matsuura N, et al. (2001) Immunological detection of a novel advanced glycation end-product. Mol. Med. 7: 783–791.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Habeeb AFSA. (1963) Determination of free amino groups in proteins by trinitrobenzenesulfonic acid. Anal. Biochem. 14: 328–336.CrossRefGoogle Scholar
  12. 12.
    Yamagishi S, Edelstein D, Du XL, et al. (2001) Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein-1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A. J. Biol. Chem. 276: 25096–25100.CrossRefPubMedGoogle Scholar
  13. 13.
    Yamagishi S, Edelstein D, Du XL, Brownlee M. (2001) Hyperglycemia potentiates collagen-induced platelet activation through mitochondrial superoxide overproduction. Diabetes 50: 1491–1494.CrossRefPubMedGoogle Scholar
  14. 14.
    Yamagishi S, Fujimori H, Yonekura H, et al. (1998) Advanced glycation endproducts inhibit prostacyclin production and induce plasminogen activator inhibitor-1 in human microvascular endothelial cells. Diabetologia 41: 1435–1441.CrossRefPubMedGoogle Scholar
  15. 15.
    Yamagishi S, Yonekura H, Yamamoto Y, et al. (1999) Vascular endothelial growth factor acts as a pericyte mitogen under hypoxic conditions. Lab. Invest. 79: 501–509.PubMedGoogle Scholar
  16. 16.
    Yamagishi S, Yonekura H, Yamamoto Y, et al. (1997) Advanced glycation end products-driven angiogenesis in vitro. Induction of the growth and tube formation of human microvascular endothelial cells through autocrine vascular endothelial growth factor. J. Biol. Chem. 272: 8723–8730.CrossRefPubMedGoogle Scholar
  17. 17.
    Yamagishi S, Yamamoto Y, Harada S, et al. (1996) Advanced glycosylation end products stimulate the growth but inhibit the prostacyclin-producing ability of endothelial cells through interactions with their receptors. FEBS Lett. 384: 103–106.CrossRefPubMedGoogle Scholar
  18. 18.
    Yamagishi S, Okamoto T, Amano S, et al. (2002) Palmitate-induced apoptosis of microvascular endothelial cells and pericytes. Mol. Med. 8: 178–183.CrossRefGoogle Scholar
  19. 19.
    Shimura H, Yamaguchi M, Kuzume M, et al. (1999) Prevention of reactive oxygen-induced endothelial cell injury by blocking its process. Eur. Surg. Res. 31: 390–398.CrossRefPubMedGoogle Scholar
  20. 20.
    Nakano H, Monden M, Umeshita K, et al. (1994) Cytoprotective effect of prostaglandin I2 analogues on superoxide-induced hepatocyte injury. Surgery 116: 883–889.PubMedGoogle Scholar
  21. 21.
    Ottonello L, Morone MP, Dapino P, Dallegri F. (1995) Tumor necrosis factor alpha-induced oxidative burst in neutrophils adherent to fibronectin: effects of cyclic AMP-elevating agents. Br. J. Haematol. 91: 566–570.CrossRefPubMedGoogle Scholar
  22. 22.
    Ii M, Hoshiga M, Fukui R, et al. (2001) Beraprost sodium regulates cell cycle in vascular smooth muscle cell through cAMP signaling by preventing down-regulation of p27 (Kip 1). Cardiovasc. Res. 52: 500–508.CrossRefPubMedGoogle Scholar
  23. 23.
    Yamagishi S, Kobayashi K, Yamamoto H. (1993) Vascular pericytes not only regulate growth, but also preserve prostacyclin-producing ability and protect against lipid peroxide-induced injury of co-cultured endothelial cells. Biochem. Biophys. Res. Commun. 190: 418–425.CrossRefPubMedGoogle Scholar
  24. 24.
    Yamagishi S, Hsu CC, Kobayashi K, Yamamoto H. (1993) Endothelin 1 mediates endothelial cell-dependent proliferation of vascular pericytes. Biochem. Biophys. Res. Commun. 191: 840–846.CrossRefPubMedGoogle Scholar

Copyright information

© NSLIJ Research Institute 2002

Authors and Affiliations

  • Sho-ichi Yamagishi
    • 1
  • Shinjiro Amano
    • 1
  • Yosuke Inagaki
    • 1
  • Tamami Okamoto
    • 1
  • Masayoshi Takeuchi
    • 2
  • Zenji Makita
    • 3
  1. 1.Division of Endocrinology and Matabolism, Department of MedicineKurume University School of MedicineKurumeJapan
  2. 2.Department of Biochemistry, Faculty of Pharmaceutical ScienceHokuriku UniversityKanazawaJapan
  3. 3.Kurume University School of MedicineKurumeJapan

Personalised recommendations