The angiotensin II type 2 receptor agonist Compound 21 is protective in experimental diabetes-associated atherosclerosis

Aims/hypothesis: 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). Methods: 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. Results: 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. Conclusions/interpretation: Taken together, these findings provide novel mechanistic and potential therapeutic insights into C21 as a monotherapy agent against DAA.