Angiotensin II subtype 2 receptor blockade and deficiency attenuate the development of atherosclerosis in an apolipoprotein E-deficient mouse model of diabetes

Aims/hypothesis: 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 (AT₂R) may modulate key processes linked to atherosclerosis. The aim of this study was to investigate the role of AT₂R 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 AT₂R 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 AT₂R 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/interpretation: This study provides evidence for AT₂R playing a role in the development of diabetes-associated atherosclerosis. These findings suggest a potential utility of AT₂R blockers in the prevention and treatment of diabetic macrovascular complications.