Advanced glycosylation endproducts block the antiproliferative effect of nitric oxide. Role in the vascular and renal complications of diabetes mellitus.

Abstract

Advanced glycosylation endproducts (AGEs) accumulate on long-lived tissue proteins such as basement membrane collagen and have been implicated in many of the long-term complications of diabetes mellitus. These products originate from glucose-derived Schiff base and Amadori products but undergo a series of complex rearrangement reactions to form ultimately protein-bound, fluorescent heterocycles. AGEs can react with and chemically inactivate nitric oxide (NO), a potent endothelial cell-derived vasodilator and antiproliferative factor. Since mesenchymal cell proliferation is an early and characteristic lesion of diabetic vasculopathy and glomerulopathy, we investigated the possibility that collagen-bound AGEs functionally inactivate the antiproliferative effect of NO. In model cell culture systems, AGEs were found to block the cytostatic effect of NO on aortic smooth muscle and renal mesangial cells. The inactivation of endothelial cell-derived NO by basement membrane AGEs may represent a common pathway in the development of the accelerated vascular and renal disease that accompany long-term diabetes mellitus. (J. Clin. Invest. 1992.

Plasma advanced glycation end products (AGEs) and NF-κB activity are independent determinants of diastolic and pulse pressure

“…This may relate in part to AGEs promoting stiffening of the aorta. Furthermore, AGEs in the vascular tissue may induce these deleterious vascular effects is by impairing nitric oxide synthase activity in endothelial cells as has been previously described [36,77,78]. As noted previously, AGEs are thought to activate the NF-κB pathway primarily as a result of their ligation with RAGE.…”

Relative contributions of advanced glycation and nitric oxide synthase inhibition to aminoguanidine-mediated renoprotection in diabetic rats

“…By contrast, other recent studies show that AGEs quench NO although the mechanisms by which this occurs are yet to be elucidated. For example, Bucala's group [52,53] showed that experimental diabetes is associated with an impaired vasodilatory response to both endotheliumdependent (acetylcholine) and endothelium independent (nitroglycerine) agents, a finding which is consistent with AGE mediated inactivation of NO within the subendothelial space. It follows then, that if AGEs mediated the effects of diabetes on the NO system, diabetes would be associated with NO deficiency rather than an excess as postulated by Williamson et al [54].…”

The cross-link breaker, N-phenacylthiazolium bromide prevents vascular advanced glycation end-product accumulation

“…Advanced glycation end products are viewed as quenching NO [14] and it is possible that the effect of PTB in attenuating the increase in blood pressure in the diabetic rats was related to reduced AGE accumulation leading to enhanced action of the vasodilator NO. By contrast, there seemed to be an unexplainable increase in blood pressure with PTB treatment in control rats.…”