title: Delayed intervention with AGE inhibitors attenuates the progression of diabetes-accelerated atherosclerosis in diabetic apolipoprotein E knockout mice.
abstract: OBJECTIVE
  Formation of AGEs is increased in the diabetic milieu, which contributes to accelerated atherogenesis. We studied whether delayed treatment with AGE-inhibiting compounds, alagebrium chloride and pyridoxamine dihydrochloride, affected established atherosclerosis in experimental diabetes in comparison with the angiotensin-converting enzyme inhibitor, quinapril.
  
  
  METHODS
  Streptozotocin-induced diabetic male Apoe (-/-) mice (n = 24 per group) received, by oral gavage, from week 10 to 20 of diabetes: no treatment; alagebrium (1 mg kg(-1) day(-1)); pyridoxamine (1 g/l in drinking water); or quinapril (30 mg kg(-1) day(-1)). Atherosclerotic lesion area (en face analysis) was evaluated for all groups.
  
  
  RESULTS
  Delayed intervention with alagebrium decreased plaque area in the diabetic Apoe (-/-) mice compared with untreated mice (total plaque area: alagebrium 10.6 ± 1.6%, untreated, 15.1 ± 1.5%, p < 0.05). This anti-atherosclerotic effect was comparable with that achieved with quinapril (quinapril 8.4 ± 1.4%, vs untreated, p < 0.05). Pyridoxamine also attenuated plaque development in diabetic mice (5.7 ± 1.2% vs untreated 11.9 ± 1.1%, p < 0.05). The anti-atherosclerotic effect conferred by alagebrium and quinapril was associated with a significant reduction in vascular oxidative stress and circulating AGEs and methylglyoxal, although preformed AGEs were not removed from the vascular wall with either delayed intervention.
  
  
  CONCLUSIONS
  Inhibition of AGE accumulation, using a delayed intervention with alagebrium or pyridoxamine, significantly attenuated the progression of established diabetes-associated atherosclerosis, similar to results obtained with quinapril. These findings provide further evidence that blockade of AGE-mediated pathways may present a novel therapy for the prevention of atherosclerosis in diabetes.
authors.affiliation: Diabetes Division, Baker IDI Heart & Diabetes Institute, PO Box 6492, St Kilda Road Central, Melbourne, VIC, 8008, Australia.
authors.forename: A M D
authors.initials: AM
authors.lastname: Watson
authors.forename: A
authors.initials: A
authors.lastname: Soro-Paavonen
authors.forename: K
authors.initials: K
authors.lastname: Sheehy
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: A C
authors.initials: AC
authors.lastname: Calkin
authors.forename: A
authors.initials: A
authors.lastname: Koitka
authors.forename: S N
authors.initials: SN
authors.lastname: Rajan
authors.forename: D
authors.initials: D
authors.lastname: Brasacchio
authors.forename: T J
authors.initials: TJ
authors.lastname: Allen
authors.forename: M E
authors.initials: ME
authors.lastname: Cooper
authors.forename: M C
authors.initials: MC
authors.lastname: Thomas
authors.forename: K J A
authors.initials: KJ
authors.lastname: Jandeleit-Dahm
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy* / Q000209:etiology*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D007703:Peptidyl-Dipeptidase A / Q000097:blood; D000077583:Quinapril; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044005:Tetrahydroisoquinolines / Q000627:therapeutic use
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D001057:Apolipoproteins E; D044005:Tetrahydroisoquinolines; D007703:Peptidyl-Dipeptidase A; D000077583:Quinapril