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

A Koitka, Z. Cao, P. Koh, A. M D Watson, K. C. Sourris, Laurent Loufrani, A Soro-Paavonen, T Walther, K. J. Woollard, K. A M Jandeleit-Dahm, M. E. Cooper, T. J. Allen

Research output: Contribution to journalArticleResearchpeer-review

28 Citations (Scopus)

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 (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.

Original languageEnglish
Pages (from-to)584-592
Number of pages9
JournalDiabetologia
Volume53
Issue number3
DOIs
Publication statusPublished - Mar 2010
Externally publishedYes

Keywords

  • Apoe-KO mouse
  • ATR
  • Atherosclerosis
  • Diabetes

Cite this

@article{bb94b9333b9c4a2caee0e508fdcd3634,
title = "Angiotensin II subtype 2 receptor blockade and deficiency attenuate the development of atherosclerosis in an apolipoprotein E-deficient mouse model of diabetes",
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 (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.",
keywords = "Apoe-KO mouse, ATR, Atherosclerosis, Diabetes",
author = "A Koitka and Z. Cao and P. Koh and Watson, {A. M D} and Sourris, {K. C.} and Laurent Loufrani and A Soro-Paavonen and T Walther and Woollard, {K. J.} and Jandeleit-Dahm, {K. A M} and Cooper, {M. E.} and Allen, {T. J.}",
year = "2010",
month = "3",
doi = "10.1007/s00125-009-1619-x",
language = "English",
volume = "53",
pages = "584--592",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Springer-Verlag London Ltd.",
number = "3",

}

Angiotensin II subtype 2 receptor blockade and deficiency attenuate the development of atherosclerosis in an apolipoprotein E-deficient mouse model of diabetes. / Koitka, A; Cao, Z.; Koh, P.; Watson, A. M D; Sourris, K. C.; Loufrani, Laurent; Soro-Paavonen, A; Walther, T; Woollard, K. J.; Jandeleit-Dahm, K. A M; Cooper, M. E.; Allen, T. J.

In: Diabetologia, Vol. 53, No. 3, 03.2010, p. 584-592.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Angiotensin II subtype 2 receptor blockade and deficiency attenuate the development of atherosclerosis in an apolipoprotein E-deficient mouse model of diabetes

AU - Koitka, A

AU - Cao, Z.

AU - Koh, P.

AU - Watson, A. M D

AU - Sourris, K. C.

AU - Loufrani, Laurent

AU - Soro-Paavonen, A

AU - Walther, T

AU - Woollard, K. J.

AU - Jandeleit-Dahm, K. A M

AU - Cooper, M. E.

AU - Allen, T. J.

PY - 2010/3

Y1 - 2010/3

N2 - 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.

AB - 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.

KW - Apoe-KO mouse

KW - ATR

KW - Atherosclerosis

KW - Diabetes

UR - http://www.scopus.com/inward/record.url?scp=77949275835&partnerID=8YFLogxK

U2 - 10.1007/s00125-009-1619-x

DO - 10.1007/s00125-009-1619-x

M3 - Article

VL - 53

SP - 584

EP - 592

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 3

ER -