Incadronate disodium inhibits advanced glycation end products-induced angiogenesis in vitro.
We have previously shown that advanced glycation end products (AGE), senescent macroprotein derivatives formed at an accelerated rate in diabetes, induced angiogenesis through overgeneration of autocrine vascular endothelial growth factor (VEGF). In the present study, effects of incadronate disodium, a nitrogen-containing bisphosphonate on AGE-elicited angiogenesis in vitro, were studied. Incadronate disodium was found to completely inhibit AGE-induced increase in DNA synthesis as well as tube formation of human microvascular endothelial cells (EC). Furthermore, incadronate disodium significantly prevented transcriptional activation of nuclear factor-kappaB and activator protein-1 and the subsequent up-regulation of VEGF mRNA levels in AGE-exposed EC. Farnesyl pyrophosphate, but not geranylgeranyl pyrophosphate, was found to completely restore the anti-angiogenic effects of incadronate disodium on EC. These results suggest that incadronate disodium could block the AGE-signaling pathway in microvascular EC through inhibition of protein farnesylation. Incadronate disodium may be a promising remedy for treatment of patients with proliferative diabetic retinopathy.
Okamoto
Tamami
T
Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, Japan.
Yamagishi
Sho-ichi
S
Inagaki
Yosuke
Y
Amano
Shinjiro
S
Takeuchi
Masayoshi
M
Kikuchi
Seiji
S
Ohno
Shigeaki
S
Yoshimura
Akihiko
A
D000818:Animals; D002478:Cells, Cultured; D004164:Diphosphonates / Q000494:pharmacology*; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D005419:Flavonoids / Q000494:pharmacology; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012717:Sesquiterpenes; D018808:Transcription Factor AP-1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D004164:Diphosphonates; D016228:Endothelial Growth Factors; D005419:Flavonoids; D017127:Glycation End Products, Advanced; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D016328:NF-kappa B; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; D018808:Transcription Factor AP-1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C071542:cimadronate; C004808:farnesyl pyrophosphate; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one