51. Angiotensin II subtype 2 receptor blockade and deficiency attenuate the development of atherosclerosis in an apolipoprotein E-deficient mouse model of diabetes.
- Author
-
Koïtka A, Cao Z, Koh P, Watson AM, Sourris KC, Loufrani L, Soro-Paavonen A, Walther T, Woollard KJ, Jandeleit-Dahm KA, Cooper ME, and Allen TJ
- Subjects
- Animals, Aorta metabolism, Aorta pathology, Body Weight, Cell Adhesion, Enzyme Inhibitors pharmacology, Imidazoles pharmacology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Pyridines pharmacology, Receptors, Angiotensin deficiency, Receptors, CCR2 metabolism, Angiotensin Receptor Antagonists, Apolipoproteins E genetics, Atherosclerosis genetics, Atherosclerosis prevention & control, Diabetes Mellitus, Experimental metabolism
- Abstract
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 (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/interpretation: 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.
- Published
- 2010
- Full Text
- View/download PDF