Abstract
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 language | English |
|---|---|
| Pages (from-to) | 780-788 |
| Number of pages | 9 |
| Journal | Journal of Hypertension |
| Volume | 28 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Apr 2010 |
| Externally published | Yes |
Keywords
- Diabetic complications
- Endothelium
- Glycation/advanced glycation end-products
- Nitric oxide
Cite this
}
Advanced glycation end-products induce vascular dysfunction via resistance to nitric oxide and suppression of endothelial nitric oxide synthase. / Soro-Paavonen, Aino; Zhang, Wei Zeng; Venardos, Kylie; Coughlan, Melinda T.; Harris, Emma; Tong, David C K; Brasacchio, Daniella; Paavonen, Karri; Chin-Dusting, Jaye; Cooper, Mark E.; Kaye, David; Thomas, Merlin C.; Forbes, Josephine M.
In: Journal of Hypertension, Vol. 28, No. 4, 04.2010, p. 780-788.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Advanced glycation end-products induce vascular dysfunction via resistance to nitric oxide and suppression of endothelial nitric oxide synthase
AU - Soro-Paavonen, Aino
AU - Zhang, Wei Zeng
AU - Venardos, Kylie
AU - Coughlan, Melinda T.
AU - Harris, Emma
AU - Tong, David C K
AU - Brasacchio, Daniella
AU - Paavonen, Karri
AU - Chin-Dusting, Jaye
AU - Cooper, Mark E.
AU - Kaye, David
AU - Thomas, Merlin C.
AU - Forbes, Josephine M.
PY - 2010/4
Y1 - 2010/4
N2 - 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.
AB - 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.
KW - Diabetic complications
KW - Endothelium
KW - Glycation/advanced glycation end-products
KW - Nitric oxide
UR - http://www.scopus.com/inward/record.url?scp=77956819409&partnerID=8YFLogxK
U2 - 10.1097/HJH.0b013e328335043e
DO - 10.1097/HJH.0b013e328335043e
M3 - Article
C2 - 20186099
AN - SCOPUS:77956819409
VL - 28
SP - 780
EP - 788
JO - Journal of Hypertension
JF - Journal of Hypertension
SN - 0263-6352
IS - 4
ER -