title: 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.
authors.affiliation: Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Ando
authors.forename: Seiji
authors.initials: S
authors.lastname: Ueda
authors.forename: Sho-ichi
authors.initials: S
authors.lastname: Yamagishi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyazaki
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kaida
authors.forename: Kumiko
authors.initials: K
authors.lastname: Kaifu
authors.forename: Miyuki
authors.initials: M
authors.lastname: Yokoro
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Nakayama
authors.forename: Nana
authors.initials: N
authors.lastname: Obara
authors.forename: Kei
authors.initials: K
authors.lastname: Fukami
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Seiya
authors.initials: S
authors.lastname: Okuda
mesh_terms: D000368:Aged; D000581:Amidohydrolases / Q000378:metabolism*; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism; D002478:Cells, Cultured; D003928:Diabetic Nephropathies / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014652:Vascular Diseases / Q000378:metabolism*
chemical_list: D017127:Glycation End Products, Advanced; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D000581:Amidohydrolases; C059999:dimethylargininase
keywords: Atherosclerosis; endothelial dysfunction; nitric oxide; oxidative stress