Advanced glycation end-products induce vascular dysfunction via resistance to nitric oxide and suppression of endothelial nitric oxide synthase

Aino Soro-Paavonen, Wei Zeng Zhang, Kylie Venardos, Melinda T. Coughlan, Emma Harris, David C K Tong, Daniella Brasacchio, Karri Paavonen, Jaye Chin-Dusting, Mark E. Cooper, David Kaye, Merlin C. Thomas, Josephine M. Forbes

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Objective: A number of factors contribute to diabetesassociated vascular dysfunction. In the present study, we tested whether exposure to advanced glycation endproducts (AGEs) impairs vascular reactivity independently of hyperglycemia and examined the potential mechanisms responsible for diabetes and AGE-associated vascular dysfunction. Methods: Vasodilator function was studied using infusion of exogenous AGEs into Sprague-Dawley rats as compared with control and streptozotocin-induced diabetic rats all followed for 16 weeks (nU10 per group). The level of arginine metabolites and expression of endothelial nitric oxide synthase (eNOS) and downstream mediators of nitric oxide-dependent signaling were examined. To further explore these mechanisms, cultured bovine aortic endothelial cells (BAECs) were exposed to AGEs. Results: Both diabetic and animals infused with AGEmodified rat serum albumin (AGE-RSA) had significantly impaired vasodilatory response to acetylcholine. Unlike diabetes-associated endothelial dysfunction, AGE infusion was not associated with changes in plasma arginine metabolites, asymmetric dimethyl-L-arginine levels or eNOS expression. However, expression of the downstream mediator cGMP-dependent protein kinase 1 (PKG-1) was significantly reduced by both AGE exposure and diabetes. AGEs also augmented hyperglycemia-associated depletion in endothelial nitric oxide production and eNOS protein expression in vitro, and the novel AGE inhibitor, alagebrium chloride, partly restored these parameters. Conclusion: We demonstrate that AGEs represent a potentially important cause of vascular dysfunction, linked to the induction of nitric oxide resistance. These findings also emphasize the deleterious and potentially additive effects of AGEs and hyperglycemia in diabetic vasculature.

Original languageEnglish
Pages (from-to)780-788
Number of pages9
JournalJournal of Hypertension
Issue number4
Publication statusPublished - Apr 2010
Externally publishedYes


  • Diabetic complications
  • Endothelium
  • Glycation/advanced glycation end-products
  • Nitric oxide

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