Angiotensin II subtype 2 receptor blockade and deficiency attenuate the development of atherosclerosis in an apolipoprotein E-deficient mouse model of diabetes.
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.
Koïtka
A
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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
Cao
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Z
Koh
P
P
Watson
A M D
AM
Sourris
K C
KC
Loufrani
L
L
Soro-Paavonen
A
A
Walther
T
T
Woollard
K J
KJ
Jandeleit-Dahm
K A M
KA
Cooper
M E
ME
Allen
T J
TJ
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
D057911:Angiotensin Receptor Antagonists; D001057:Apolipoproteins E; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D011945:Receptors, Angiotensin; D054390:Receptors, CCR2; C073402:PD 123319