Impairment of vascular endothelial nitric oxide synthase activity by advanced glycation end products.
Endothelial damage is believed to play a key role in the development of both micro- and macrovascular disease in diabetes, and advanced glycation end products (AGEs) may contribute importantly to this. To determine whether glucose-derived AGEs can cause endothelial dysfunction, we examined the effects of albumin AGE-modified by glucose (AGE-Glu) both in vivo, after injection into rabbit femoral artery, and in vitro on rabbit aortic rings and cultured human umbilical vein endothelial cells (HUVEC). Exposure of blood vessels to AGE-Glu, in vivo and in vitro, inhibited endothelium-dependent vasorelaxation, whereas unmodified albumin did not. In isolated rabbit aorta, this effect was reversible after AGE-Glu washout, and the response to the endothelium-independent vasodilator sodium nitroprusside was unaffected by AGE-Glu. In HUVEC, AGE-Glu inhibited endothelial nitric oxide synthase activity, and this was associated with a decrease in serine phosphorylation of this enzyme. Longer term (72 h) incubation decreased HUVEC viability. Use of specific antibodies demonstrated that these effects were mediated by N(epsilon)-(carboxymethyl)lysine (CML), an important AGE found in vivo, and by the AGE-R1 receptor. Furthermore, these effects all occurred at CML concentrations similar to those found in the plasma of diabetic patients. These results suggest an important role of AGE in the pathogenesis of diabetic vasculopathy.
Center for Cardiovascular Biology and Medicine, King's College London, London SE1 1UL, UK.
Biao
B
Xu
Rakesh
R
Chibber
Daniel
D
Ruggiero
Eva
E
Kohner
James
J
Ritter
Albert
A
Ferro
Daniel
D
Ruggerio
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001120:Arginine / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002478:Cells, Cultured; D002956:Citrulline / Q000096:biosynthesis; D003920:Diabetes Mellitus / Q000097:blood; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005263:Femoral Artery / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008239:Lysine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000097:blood / Q000276:immunology; D008297:Male; D008954:Models, Biological; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D011817:Rabbits; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000276:immunology; D014664:Vasodilation / Q000187:drug effects
D000906:Antibodies; D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D002956:Citrulline; D009569:Nitric Oxide; C048496:N(6)-carboxymethyllysine; D001120:Arginine; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D008239:Lysine; D019331:NG-Nitroarginine Methyl Ester