title: The angiotensin II type 2 receptor agonist Compound 21 is protective in experimental diabetes-associated atherosclerosis.
abstract: Angiotensin II is well-recognised to be a key mediator in driving the pathological events of diabetes-associated atherosclerosis via signalling through its angiotensin II type 1 receptor (AT1R) subtype. However, its actions via the angiotensin II type 2 receptor (AT2R) subtype are still poorly understood. This study is the first to investigate the role of the novel selective AT2R agonist, Compound 21 (C21) in an experimental model of diabetes-associated atherosclerosis (DAA).
  
  
  
  Streptozotocin-induced diabetic Apoe-knockout mice were treated with vehicle (0.1 mol/l citrate buffer), C21 (1 mg/kg per day), candesartan cilexetil (4 mg/kg per day) or C21 + candesartan cilexetil over a 20 week period. In vitro models of DAA using human aortic endothelial cells and monocyte cultures treated with C21 were also performed. At the end of the experiments, assessment of plaque content and markers of oxidative stress, inflammation and fibrosis were conducted.
  
  
  
  C21 treatment significantly attenuated aortic plaque deposition in a mouse model of DAA in vivo, in association with a decreased infiltration of macrophages and mediators of inflammation, oxidative stress and fibrosis. On the other hand, combination therapy with C21 and candesartan (AT1R antagonist) appeared to have a limited additive effect in attenuating the pathology of DAA when compared with either treatment alone. Similarly, C21 was found to confer profound anti-atherosclerotic actions at the in vitro level, particularly in the setting of hyperglycaemia. Strikingly, these atheroprotective actions of C21 were completely blocked by the AT2R antagonist PD123319.
  
  
  
  Taken together, these findings provide novel mechanistic and potential therapeutic insights into C21 as a monotherapy agent against DAA.
authors.affiliation: JDRF Danielle Alberti Memorial Centre for Diabetic Complications, Diabetic Complications Division, Baker IDI Heart and Diabetes Research Institute, 75 Commercial Road, P. O. Box 6492, Melbourne, VIC, 3004, Australia.
authors.forename: Bryna S M
authors.initials: BS
authors.lastname: Chow
authors.affiliation: JDRF Danielle Alberti Memorial Centre for Diabetic Complications, Diabetic Complications Division, Baker IDI Heart and Diabetes Research Institute, 75 Commercial Road, P. O. Box 6492, Melbourne, VIC, 3004, Australia.
authors.forename: Christine
authors.initials: C
authors.lastname: Koulis
authors.affiliation: JDRF Danielle Alberti Memorial Centre for Diabetic Complications, Diabetic Complications Division, Baker IDI Heart and Diabetes Research Institute, 75 Commercial Road, P. O. Box 6492, Melbourne, VIC, 3004, Australia.
authors.forename: Pooja
authors.initials: P
authors.lastname: Krishnaswamy
authors.affiliation: IMM-Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark.
authors.forename: Ulrike M
authors.initials: UM
authors.lastname: Steckelings
authors.affiliation: School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands.
authors.forename: Thomas
authors.initials: T
authors.lastname: Unger
authors.affiliation: JDRF Danielle Alberti Memorial Centre for Diabetic Complications, Diabetic Complications Division, Baker IDI Heart and Diabetes Research Institute, 75 Commercial Road, P. O. Box 6492, Melbourne, VIC, 3004, Australia.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
authors.affiliation: JDRF Danielle Alberti Memorial Centre for Diabetic Complications, Diabetic Complications Division, Baker IDI Heart and Diabetes Research Institute, 75 Commercial Road, P. O. Box 6492, Melbourne, VIC, 3004, Australia.
authors.forename: Karin A
authors.initials: KA
authors.lastname: Jandeleit-Dahm
authors.affiliation: JDRF Danielle Alberti Memorial Centre for Diabetic Complications, Diabetic Complications Division, Baker IDI Heart and Diabetes Research Institute, 75 Commercial Road, P. O. Box 6492, Melbourne, VIC, 3004, Australia. terri.allen@bakeridi.edu.au.
authors.forename: Terri J
authors.initials: TJ
authors.lastname: Allen
mesh_terms: D057912:Angiotensin II Type 2 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000209:etiology* / Q000517:prevention & control*; D001562:Benzimidazoles / Q000627:therapeutic use; D001713:Biphenyl Compounds / Q000627:therapeutic use; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D013449:Sulfonamides / Q000627:therapeutic use*; D013777:Tetrazoles / Q000627:therapeutic use; D013876:Thiophenes / Q000627:therapeutic use*
chemical_list: D057912:Angiotensin II Type 2 Receptor Blockers; D001057:Apolipoproteins E; D001562:Benzimidazoles; D001713:Biphenyl Compounds; C494557:N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide; D044139:Receptor, Angiotensin, Type 2; D013449:Sulfonamides; D013777:Tetrazoles; D013876:Thiophenes; C077793:candesartan cilexetil; C081643:candesartan
keywords: AT2 receptor; Angiotensin II; Atherosclerosis; Compound 21; Diabetes