Exogenous advanced glycosylation end products induce complex vascular dysfunction in normal animals: a model for diabetic and aging complications.
Advanced glycosylation end products (AGEs) have been implicated in many of the complications of diabetes and normal aging. Markedly elevated vascular tissue and circulating AGEs were linked recently to the accelerated vasculopathy of end-stage diabetic renal disease. To determine the pathogenic role of AGEs in vivo, AGE-modified albumin was administered to healthy nondiabetic rats and rabbits alone or in combination with the AGE-crosslink inhibitor aminoguanidine. Within 2-4 weeks of AGE treatment, the AGE content of aortic tissue samples rose to six times the amount found in controls (P < 0.001). Cotreatment with aminoguanidine limited tissue AGE accumulation to levels two times that of control. AGE administration was associated with a significant increase in vascular permeability, as assessed by 125I label tracer methods. This alteration was absent in animals that received aminoguanidine in addition to AGE. Significant mononuclear cell migratory activity was observed in subendothelial and periarteriolar spaces in various tissues from AGE-treated rats compared to normal cellularity noted in tissues from animals treated with aminoguanidine. Blood pressure studies of AGE-treated rats and rabbits revealed markedly defective vasodilatory responses to acetylcholine and nitroglycerin compared to controls (P < 0.001), consistent with marked NO. inactivation; aminoguanidine treatment significantly prevented this defect. These in vivo data demonstrate directly that AGEs, independent of metabolic or genetic factors, can induce complex vascular alterations resembling those seen in diabetes or aging. AGE administration represents an animal model system for the study of diabetic and aging complications as well as for assessing the efficacy of newly emerging therapies aimed at inhibiting advanced glycosylation.
Vlassara
H
H
Picower Institute for Medical Research, Manhasset, NY 11030.
Fuh
H
H
Makita
Z
Z
Krungkrai
S
S
Cerami
A
A
Bucala
R
R
D000109:Acetylcholine / Q000494:pharmacology; D000375:Aging; D000818:Animals; D001794:Blood Pressure; D002199:Capillary Permeability; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008954:Models, Biological; D009000:Monocytes / Q000166:cytology; D005996:Nitroglycerin / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011917:Rats, Inbred Lew; D014664:Vasodilation / Q000187:drug effects
D017127:Glycation End Products, Advanced; D005996:Nitroglycerin; D000109:Acetylcholine