Loss of angiotensin-converting enzyme-2 exacerbates diabetic cardiovascular complications and leads to systolic and vascular dysfunction: A critical role of the angiotensin II/AT1 receptor axis

Vaibhav B. Patel, Sreedhar Bodiga, Ratnadeep Basu, Subhash K. Das, Wang Wang, Zuocheng Wang, Jennifer Lo, Maria B. Grant, Jiuchang Zhong, Zamaneh Kassiri, Gavin Y. Oudit

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

Rationale: Diabetic cardiovascular complications are reaching epidemic proportions. Angiotensin-converting enzyme-2 (ACE2) is a negative regulator of the renin-angiotensin system. We hypothesize that loss of ACE2 exacerbates cardiovascular complications induced by diabetes. Objective: To define the role of ACE2 in diabetic cardiovascular complications. Methods and Results: We used the well-validated Akita mice, a model of human diabetes, and generated double-mutant mice using the ACE2 knockout (KO) mice (Akita/ACE2 -/y). Diabetic state was associated with increased ACE2 in Akita mice, whereas additional loss of ACE2 in these mice leads to increased plasma and tissue angiotensin II levels, resulting in systolic dysfunction on a background of impaired diastolic function. Downregulation of SERCA2 and lipotoxicity were equivalent in Akita and Akita/ACE2KO hearts and are likely mediators of the diastolic dysfunction. However, greater activation of protein kinase C and loss of Akt and endothelial nitric oxide synthase phosphorylation occurred in the Akita/ACE2KO hearts. Systolic dysfunction in Akita/ACE2KO mice was linked to enhanced activation of NADPH oxidase and metalloproteinases, resulting in greater oxidative stress and degradation of the extracellular matrix. Impaired flow-mediated dilation in vivo correlated with increased vascular oxidative stress in Akita/ACE2KO mice. Treatment with the AT1 receptor blocker, irbesartan rescued the systolic dysfunction, normalized altered signaling pathways, flow-mediated dilation, and the increased oxidative stress in the cardiovascular system. Conclusions: Loss of ACE2 disrupts the balance of the renin-angiotensin system in a diabetic state and leads to an angiotensin II/AT1 receptor-dependent systolic dysfunction and impaired vascular function. Our study demonstrates that ACE2 serves as a protective mechanism against diabetes-induced cardiovascular complications.

Original languageEnglish (US)
Pages (from-to)1322-1335
Number of pages14
JournalCirculation Research
Volume110
Issue number10
DOIs
StatePublished - May 11 2012
Externally publishedYes

Fingerprint

Angiotensin Type 1 Receptor
Angiotensin Receptors
Diabetes Complications
Blood Vessels
Oxidative Stress
irbesartan
Renin-Angiotensin System
Dilatation
angiotensin converting enzyme 2
Nitric Oxide Synthase Type III
NADPH Oxidase
Metalloproteases
Cardiovascular System
Knockout Mice
Angiotensin II
Protein Kinase C
Extracellular Matrix
Down-Regulation
Phosphorylation

Keywords

  • angiotensin II
  • angiotensin-converting enzyme-2
  • AT1 receptor
  • diabetes
  • renin angiotensin system

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Loss of angiotensin-converting enzyme-2 exacerbates diabetic cardiovascular complications and leads to systolic and vascular dysfunction : A critical role of the angiotensin II/AT1 receptor axis. / Patel, Vaibhav B.; Bodiga, Sreedhar; Basu, Ratnadeep; Das, Subhash K.; Wang, Wang; Wang, Zuocheng; Lo, Jennifer; Grant, Maria B.; Zhong, Jiuchang; Kassiri, Zamaneh; Oudit, Gavin Y.

In: Circulation Research, Vol. 110, No. 10, 11.05.2012, p. 1322-1335.

Research output: Contribution to journalArticle

Patel, Vaibhav B. ; Bodiga, Sreedhar ; Basu, Ratnadeep ; Das, Subhash K. ; Wang, Wang ; Wang, Zuocheng ; Lo, Jennifer ; Grant, Maria B. ; Zhong, Jiuchang ; Kassiri, Zamaneh ; Oudit, Gavin Y. / Loss of angiotensin-converting enzyme-2 exacerbates diabetic cardiovascular complications and leads to systolic and vascular dysfunction : A critical role of the angiotensin II/AT1 receptor axis. In: Circulation Research. 2012 ; Vol. 110, No. 10. pp. 1322-1335.
@article{fc656454da234e4b915392a0e8cd392e,
title = "Loss of angiotensin-converting enzyme-2 exacerbates diabetic cardiovascular complications and leads to systolic and vascular dysfunction: A critical role of the angiotensin II/AT1 receptor axis",
abstract = "Rationale: Diabetic cardiovascular complications are reaching epidemic proportions. Angiotensin-converting enzyme-2 (ACE2) is a negative regulator of the renin-angiotensin system. We hypothesize that loss of ACE2 exacerbates cardiovascular complications induced by diabetes. Objective: To define the role of ACE2 in diabetic cardiovascular complications. Methods and Results: We used the well-validated Akita mice, a model of human diabetes, and generated double-mutant mice using the ACE2 knockout (KO) mice (Akita/ACE2 -/y). Diabetic state was associated with increased ACE2 in Akita mice, whereas additional loss of ACE2 in these mice leads to increased plasma and tissue angiotensin II levels, resulting in systolic dysfunction on a background of impaired diastolic function. Downregulation of SERCA2 and lipotoxicity were equivalent in Akita and Akita/ACE2KO hearts and are likely mediators of the diastolic dysfunction. However, greater activation of protein kinase C and loss of Akt and endothelial nitric oxide synthase phosphorylation occurred in the Akita/ACE2KO hearts. Systolic dysfunction in Akita/ACE2KO mice was linked to enhanced activation of NADPH oxidase and metalloproteinases, resulting in greater oxidative stress and degradation of the extracellular matrix. Impaired flow-mediated dilation in vivo correlated with increased vascular oxidative stress in Akita/ACE2KO mice. Treatment with the AT1 receptor blocker, irbesartan rescued the systolic dysfunction, normalized altered signaling pathways, flow-mediated dilation, and the increased oxidative stress in the cardiovascular system. Conclusions: Loss of ACE2 disrupts the balance of the renin-angiotensin system in a diabetic state and leads to an angiotensin II/AT1 receptor-dependent systolic dysfunction and impaired vascular function. Our study demonstrates that ACE2 serves as a protective mechanism against diabetes-induced cardiovascular complications.",
keywords = "angiotensin II, angiotensin-converting enzyme-2, AT1 receptor, diabetes, renin angiotensin system",
author = "Patel, {Vaibhav B.} and Sreedhar Bodiga and Ratnadeep Basu and Das, {Subhash K.} and Wang Wang and Zuocheng Wang and Jennifer Lo and Grant, {Maria B.} and Jiuchang Zhong and Zamaneh Kassiri and Oudit, {Gavin Y.}",
year = "2012",
month = "5",
day = "11",
doi = "10.1161/CIRCRESAHA.112.268029",
language = "English (US)",
volume = "110",
pages = "1322--1335",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "10",

}

TY - JOUR

T1 - Loss of angiotensin-converting enzyme-2 exacerbates diabetic cardiovascular complications and leads to systolic and vascular dysfunction

T2 - A critical role of the angiotensin II/AT1 receptor axis

AU - Patel, Vaibhav B.

AU - Bodiga, Sreedhar

AU - Basu, Ratnadeep

AU - Das, Subhash K.

AU - Wang, Wang

AU - Wang, Zuocheng

AU - Lo, Jennifer

AU - Grant, Maria B.

AU - Zhong, Jiuchang

AU - Kassiri, Zamaneh

AU - Oudit, Gavin Y.

PY - 2012/5/11

Y1 - 2012/5/11

N2 - Rationale: Diabetic cardiovascular complications are reaching epidemic proportions. Angiotensin-converting enzyme-2 (ACE2) is a negative regulator of the renin-angiotensin system. We hypothesize that loss of ACE2 exacerbates cardiovascular complications induced by diabetes. Objective: To define the role of ACE2 in diabetic cardiovascular complications. Methods and Results: We used the well-validated Akita mice, a model of human diabetes, and generated double-mutant mice using the ACE2 knockout (KO) mice (Akita/ACE2 -/y). Diabetic state was associated with increased ACE2 in Akita mice, whereas additional loss of ACE2 in these mice leads to increased plasma and tissue angiotensin II levels, resulting in systolic dysfunction on a background of impaired diastolic function. Downregulation of SERCA2 and lipotoxicity were equivalent in Akita and Akita/ACE2KO hearts and are likely mediators of the diastolic dysfunction. However, greater activation of protein kinase C and loss of Akt and endothelial nitric oxide synthase phosphorylation occurred in the Akita/ACE2KO hearts. Systolic dysfunction in Akita/ACE2KO mice was linked to enhanced activation of NADPH oxidase and metalloproteinases, resulting in greater oxidative stress and degradation of the extracellular matrix. Impaired flow-mediated dilation in vivo correlated with increased vascular oxidative stress in Akita/ACE2KO mice. Treatment with the AT1 receptor blocker, irbesartan rescued the systolic dysfunction, normalized altered signaling pathways, flow-mediated dilation, and the increased oxidative stress in the cardiovascular system. Conclusions: Loss of ACE2 disrupts the balance of the renin-angiotensin system in a diabetic state and leads to an angiotensin II/AT1 receptor-dependent systolic dysfunction and impaired vascular function. Our study demonstrates that ACE2 serves as a protective mechanism against diabetes-induced cardiovascular complications.

AB - Rationale: Diabetic cardiovascular complications are reaching epidemic proportions. Angiotensin-converting enzyme-2 (ACE2) is a negative regulator of the renin-angiotensin system. We hypothesize that loss of ACE2 exacerbates cardiovascular complications induced by diabetes. Objective: To define the role of ACE2 in diabetic cardiovascular complications. Methods and Results: We used the well-validated Akita mice, a model of human diabetes, and generated double-mutant mice using the ACE2 knockout (KO) mice (Akita/ACE2 -/y). Diabetic state was associated with increased ACE2 in Akita mice, whereas additional loss of ACE2 in these mice leads to increased plasma and tissue angiotensin II levels, resulting in systolic dysfunction on a background of impaired diastolic function. Downregulation of SERCA2 and lipotoxicity were equivalent in Akita and Akita/ACE2KO hearts and are likely mediators of the diastolic dysfunction. However, greater activation of protein kinase C and loss of Akt and endothelial nitric oxide synthase phosphorylation occurred in the Akita/ACE2KO hearts. Systolic dysfunction in Akita/ACE2KO mice was linked to enhanced activation of NADPH oxidase and metalloproteinases, resulting in greater oxidative stress and degradation of the extracellular matrix. Impaired flow-mediated dilation in vivo correlated with increased vascular oxidative stress in Akita/ACE2KO mice. Treatment with the AT1 receptor blocker, irbesartan rescued the systolic dysfunction, normalized altered signaling pathways, flow-mediated dilation, and the increased oxidative stress in the cardiovascular system. Conclusions: Loss of ACE2 disrupts the balance of the renin-angiotensin system in a diabetic state and leads to an angiotensin II/AT1 receptor-dependent systolic dysfunction and impaired vascular function. Our study demonstrates that ACE2 serves as a protective mechanism against diabetes-induced cardiovascular complications.

KW - angiotensin II

KW - angiotensin-converting enzyme-2

KW - AT1 receptor

KW - diabetes

KW - renin angiotensin system

UR - http://www.scopus.com/inward/record.url?scp=84861099242&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84861099242&partnerID=8YFLogxK

U2 - 10.1161/CIRCRESAHA.112.268029

DO - 10.1161/CIRCRESAHA.112.268029

M3 - Article

C2 - 22474255

AN - SCOPUS:84861099242

VL - 110

SP - 1322

EP - 1335

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 10

ER -