title: Angiotensin II subtype 2 receptor blockade and deficiency attenuate the development of atherosclerosis in an apolipoprotein E-deficient mouse model of diabetes.
abstract: OBJECTIVE
  Most of the known actions of angiotensin II have been considered primarily to be the result of angiotensin II subtype 1 receptor activation. However, recent data suggest that the angiotensin II subtype 2 receptor (AT(2)R) may modulate key processes linked to atherosclerosis. The aim of this study was to investigate the role of AT(2)R in diabetes-associated atherosclerosis using pharmacological blockade and genetic deficiency.
  
  
  METHODS
  Aortic plaque deposition was assessed in streptozotocin-induced diabetic apolipoprotein E (Apoe) knockout (KO) and At ( 2 ) r (also known as Agtr2)/Apoe double-KO (DKO) mice. Control and diabetic Apoe-KO mice received an AT(2)R antagonist PD123319 (5 mg kg(-1) day(-1)) via osmotic minipump for 20 weeks (n = 7-8 per group).
  
  
  RESULTS
  Diabetes was associated with a sixfold increase in plaque area (diabetic Apoe-KO: 12.7 +/- 1.4% vs control Apoe-KO: 2.3 +/- 0.4%, p < 0.001) as well as a significant increase in aortic expression of the gene At ( 2 ) r (also known as Agtr2). The increase in plaque area with diabetes was attenuated in AT(2)R antagonist-treated diabetic Apoe-KO mice (7.1 +/- 0.5%, p < 0.05) and in diabetic At ( 2 ) r/Apoe DKO mice (9.2 +/- 1.3%, p < 0.05). These benefits occurred independently of glycaemic control or BP, and were associated with downregulation of a range of pro-inflammatory cytokines, adhesion molecules, chemokines and various extracellular matrix proteins.
  
  
  CONCLUSIONS
  This study provides evidence for AT(2)R playing a role in the development of diabetes-associated atherosclerosis. These findings suggest a potential utility of AT(2)R blockers in the prevention and treatment of diabetic macrovascular complications.
authors: JDRF Danielle Alberti Memorial Centre for Diabetic Complications, Diabetes Division, Baker IDI Heart and Diabetes Research Institute, PO Box 6492, St Kilda Road Central, Melbourne, VIC 8008, Australia. audrey.koitka@bakeridi.edu.au
authors: A
authors: A
authors: Koïtka
authors: Z
authors: Z
authors: Cao
authors: P
authors: P
authors: Koh
authors: A M D
authors: AM
authors: Watson
authors: K C
authors: KC
authors: Sourris
authors: L
authors: L
authors: Loufrani
authors: A
authors: A
authors: Soro-Paavonen
authors: T
authors: T
authors: Walther
authors: K J
authors: KJ
authors: Woollard
authors: K A M
authors: KA
authors: Jandeleit-Dahm
authors: M E
authors: ME
authors: Cooper
authors: T J
authors: TJ
authors: Allen
mesh_terms: D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics* / Q000517:prevention & control*; D001835:Body Weight; D002448:Cell Adhesion; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011725:Pyridines / Q000494:pharmacology; D011945:Receptors, Angiotensin / Q000172:deficiency; D054390:Receptors, CCR2 / Q000378:metabolism
chemical_list: D057911:Angiotensin Receptor Antagonists; D001057:Apolipoproteins E; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D011945:Receptors, Angiotensin; D054390:Receptors, CCR2; C073402:PD 123319