Involvement of advanced glycation end product-induced asymmetric dimethylarginine generation in endothelial dysfunction

Abstract

Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, plays a role in endothelial dysfunction, an initial step of atherosclerosis. Advanced glycation end products (AGEs) also contribute to accelerated atherosclerosis. However, a pathophysiological crosstalk between ADMA and AGEs remains unclear. In this study, we investigated the relationship between ADMA and AGE level in patients with end-stage renal disease (ESRD) due to diabetic nephropathy. We also examined whether and how AGEs increased ADMA generation by cultured endothelial cells (ECs). Plasma ADMA levels were positively associated with serum AGE level and were inversely correlated with endothelial function determined by flow-mediated vasodilatation. AGEs dose dependently increased reactive oxygen species (ROS) generation in ECs, which was blocked by antisense DNA raised against receptor for AGEs (RAGE). Furthermore, AGEs decreased messenger RNA (mRNA) level of dimethylarginine dimethylaminohydrolase (DDAH)-II, an enzyme for ADMA degradation, reduced its total enzymatic activity and resultantly increased ADMA, all of which were completely blocked by an antioxidant, N-acetylcysteine. These results suggest that the AGE-RAGE-mediated ROS generation could be involved in endothelial dysfunction in diabetic ESRD patients partly by increasing the ADMA generation via suppression of DDAH activity in ECs.

Advanced Glycation End Products: A Molecular Target for Vascular Complications in Diabetes

“…Nitric oxide (NO) is the most potent endogenous vasodilator and, by the role of its antiinflammatory, antiproliferation and antithrombotic effects, it is widely recognized as an endogenous antiatherogenic factor (33)(34)(35)(36)(37)(38). We, along with others, have shown that AGEs not only inhibit endothelial NO synthase expression in endothelial cells, but they also stimulate generation of peroxynitrite, a reactive intermediate and toxic product of NO with superoxide anion (33)(34)(35).…”

“…We, along with others, have shown that AGEs not only inhibit endothelial NO synthase expression in endothelial cells, but they also stimulate generation of peroxynitrite, a reactive intermediate and toxic product of NO with superoxide anion (33)(34)(35). Furthermore, the AGE-RAGE interaction enhances the production of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase in endothelial cells, mesangial cells and renal proximal tubular cells (35)(36)(37)(38). Because ADMA is now considered one of the strongest biomarkers of CVD and chronic kidney disease progression (35), decreased production and/or impaired bioavailability of NO by the AGE-RAGE axis could also be involved in cardiorenal syndrome in diabetes.…”

Association of the roles of advanced glycation end products and osteocalcin between bone metabolism and vascular failure

“…AGEs increase intracellular oxidative stress generation and inflammation-related gene expression in vascular wall cells. AGEs inhibit endothelial nitric oxide (NO) synthase (eNOS) expression and NO production 12,13) , which is the most potent endogenous vasodilator and antiatherogenic factor. Moreover, AGEs impair endothelial cell repair, enhance apoptosis, and suppress the migration and tube formation of endothelial progenitor cells via Akt and cycloxygenase-2 inhibition 14,15) .…”

Advanced Glycation End-Products Downregulate HoxA9EC through Activation of Nuclear Factor Kappa B by Reciprocal Interaction

“…Endothelial dysfunction is thought to be a key event in the development of diabetic atherosclerosis and cardiovascular damage [1,2]. Advanced glycation end-products (AGEs), products of the nonenzymatic glycation and oxidation of proteins, have been recognized as an important pathophysiological mechanism in the dysfunction of endothelial progenitor cells (EPCs)/endothelial cells (ECs) during atherogenesis [3,4,5]. AGEs promote EPC/EC apoptosis, inhibit cell migration, and depress the capacity of tube formation; this can be mediated by the binding of AGEs and the receptor for AGEs (RAGE) [6].…”