Related Experiment Videos
Incadronate disodium inhibits advanced glycation end products-induced angiogenesis in vitro
Tamami Okamoto1, Sho-ichi Yamagishi, Yosuke Inagaki
1Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, Japan.
Abstract:
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.
Insights
Incadronate disodium inhibits advanced glycation end product (AGE)-induced angiogenesis by blocking the VEGF pathway in endothelial cells. This suggests potential for treating diabetic retinopathy.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Advanced glycation end products (AGE) accelerate in diabetes, promoting angiogenesis via vascular endothelial growth factor (VEGF).
- Proliferative diabetic retinopathy involves aberrant angiogenesis.
Purpose of the Study:
- To investigate the anti-angiogenic effects of incadronate disodium on AGE-induced responses in vitro.
- To elucidate the molecular mechanisms underlying incadronate disodium's action.
Main Methods:
- In vitro assessment of DNA synthesis and tube formation in human microvascular endothelial cells (EC).
- Analysis of nuclear factor-kappaB (NF-kB) and activator protein-1 (AP-1) transcriptional activation.
- Investigation of VEGF mRNA levels and the role of protein prenylation (farnesyl pyrophosphate and geranylgeranyl pyrophosphate).
Main Results:
- Incadronate disodium completely inhibited AGE-induced DNA synthesis and EC tube formation.
- It prevented transcriptional activation of NF-kB and AP-1, reducing VEGF mRNA upregulation.
- Farnesyl pyrophosphate, but not geranylgeranyl pyrophosphate, restored the anti-angiogenic effect.
Conclusions:
- Incadronate disodium blocks the AGE-signaling pathway in microvascular EC by inhibiting protein farnesylation.
- This drug shows promise as a therapeutic agent for proliferative diabetic retinopathy.