Advanced glycation end-products induce vascular dysfunction via resistance to nitric oxide and suppression of endothelial nitric oxide synthase.
OBJECTIVE
A number of factors contribute to diabetes-associated vascular dysfunction. In the present study, we tested whether exposure to advanced glycation end-products (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 (n = 10 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 AGE-modified 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.


CONCLUSIONS
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.
Soro-Paavonen
Aino
A
JDRF Einstein Centre for Diabetes Complications, Melbourne, Australia.
Zhang
Wei-Zeng
WZ
Venardos
Kylie
K
Coughlan
Melinda T
MT
Harris
Emma
E
Tong
David C K
DC
Brasacchio
Daniella
D
Paavonen
Karri
K
Chin-Dusting
Jaye
J
Cooper
Mark E
ME
Kaye
David
D
Thomas
Merlin C
MC
Forbes
Josephine M
JM
D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014652:Vascular Diseases / Q000139:chemically induced* / Q000150:complications / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000378:metabolism / Q000494:pharmacology
D017127:Glycation End Products, Advanced; D007004:Hypoglycemic Agents; D014665:Vasodilator Agents; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D052250:Nitric Oxide Synthase Type III