Enhanced angiotensin II-induced cardiac and aortic remodeling in ACE2 knockout mice

Mahmoud S. Alghamri, Nathan M. Weir, Mark P. Anstadt, Khalid M. Elased, Susan Gurley, Mariana Morris

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Angiotensin-converting enzyme 2 (ACE2) is present in the heart and thought to exert protective functions. We conducted studies in ACE2 deficient mice to determine whether enzyme loss would exacerbate the cardiac and vascular pathological responses to chronic subcutaneous (sc) angiotensin II (Ang II) infusion. Eight-week-old male ACE2 knockout (KO) and wild type (WT) mice were infused with Ang II (1000 ng/kg per min, 4 weeks) using mini-osmotic pumps. Blood pressure (radiotelemetry), cardiac function (echocardiography, echo), cardiac/aortic structure (histology, collagen, and oxidative stress), and vascular inflammation were examined. Before Ang II infusion, ACE2 KO mice showed unaltered cardiac function and blood pressure. After 4 weeks of Ang II infusion, the mean arterial pressure (MAP) increased from 96 ± 2 to 136 ± 17 mm Hg (∼40%) in WT and from 104 ± 5 to 141 ± 13 mm Hg (∼ 35%) in ACE2 KO. While there were no differences in MAP between groups, the ACE2 KO responded differently to the hypertensive stimulus. Echo analysis revealed severe myocardial dysfunction in Ang II-infused ACE2 KO (Ang ACE2 KO). Ejection fraction was lower (39% versus 50%) as was fractional shortening (27% versus 38%) in ACE2 KO versus WT, respectively. Cardiac dysfunction was associated with hypertrophic cardiomyopathy shown by increased left-ventricular wall thickness, average cardiomyocyte cross-sectional area, and heart weight/body weight ratio. Collagen staining in the myocardium and aorta revealed increased collagen in Ang ACE2 KO, suggestive of remodeling. Results also showed enhanced oxidative stress in the myocardium and aorta of Ang ACE2 KO. There was a 3-fold elevation in macrophage inflammatory protein 1α (MIP 1α) in the aorta of ACE2 KO. Studies in the ACE2 KO model reveal the importance of ACE2 in the maladaptive cardiac and aortic responses to Ang II stimulation, seen as enhanced remodeling using physiological, structural, and biochemical markers. Results document a cardio- and vascular-protective role of ACE2 under pathological conditions.

Original languageEnglish (US)
Pages (from-to)138-151
Number of pages14
JournalJournal of Cardiovascular Pharmacology and Therapeutics
Volume18
Issue number2
DOIs
StatePublished - Mar 1 2013
Externally publishedYes

Fingerprint

Knockout Mice
Angiotensin II
Blood Vessels
Aorta
Collagen
angiotensin converting enzyme 2
Myocardium
Arterial Pressure
Oxidative Stress
Blood Pressure
Macrophage Inflammatory Proteins
Hypertrophic Cardiomyopathy
Cardiac Myocytes
Echocardiography
Histology
Biomarkers
Body Weight
Staining and Labeling
Inflammation
Weights and Measures

Keywords

  • aorta
  • cardiac dysfunction
  • echocardiography
  • oxidative stress
  • remodeling
  • renin-angiotensin system

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine
  • Pharmacology (medical)

Cite this

Enhanced angiotensin II-induced cardiac and aortic remodeling in ACE2 knockout mice. / Alghamri, Mahmoud S.; Weir, Nathan M.; Anstadt, Mark P.; Elased, Khalid M.; Gurley, Susan; Morris, Mariana.

In: Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 18, No. 2, 01.03.2013, p. 138-151.

Research output: Contribution to journalArticle

Alghamri, Mahmoud S. ; Weir, Nathan M. ; Anstadt, Mark P. ; Elased, Khalid M. ; Gurley, Susan ; Morris, Mariana. / Enhanced angiotensin II-induced cardiac and aortic remodeling in ACE2 knockout mice. In: Journal of Cardiovascular Pharmacology and Therapeutics. 2013 ; Vol. 18, No. 2. pp. 138-151.
@article{1726c299183f41ceae99f95d1fe7b368,
title = "Enhanced angiotensin II-induced cardiac and aortic remodeling in ACE2 knockout mice",
abstract = "Angiotensin-converting enzyme 2 (ACE2) is present in the heart and thought to exert protective functions. We conducted studies in ACE2 deficient mice to determine whether enzyme loss would exacerbate the cardiac and vascular pathological responses to chronic subcutaneous (sc) angiotensin II (Ang II) infusion. Eight-week-old male ACE2 knockout (KO) and wild type (WT) mice were infused with Ang II (1000 ng/kg per min, 4 weeks) using mini-osmotic pumps. Blood pressure (radiotelemetry), cardiac function (echocardiography, echo), cardiac/aortic structure (histology, collagen, and oxidative stress), and vascular inflammation were examined. Before Ang II infusion, ACE2 KO mice showed unaltered cardiac function and blood pressure. After 4 weeks of Ang II infusion, the mean arterial pressure (MAP) increased from 96 ± 2 to 136 ± 17 mm Hg (∼40{\%}) in WT and from 104 ± 5 to 141 ± 13 mm Hg (∼ 35{\%}) in ACE2 KO. While there were no differences in MAP between groups, the ACE2 KO responded differently to the hypertensive stimulus. Echo analysis revealed severe myocardial dysfunction in Ang II-infused ACE2 KO (Ang ACE2 KO). Ejection fraction was lower (39{\%} versus 50{\%}) as was fractional shortening (27{\%} versus 38{\%}) in ACE2 KO versus WT, respectively. Cardiac dysfunction was associated with hypertrophic cardiomyopathy shown by increased left-ventricular wall thickness, average cardiomyocyte cross-sectional area, and heart weight/body weight ratio. Collagen staining in the myocardium and aorta revealed increased collagen in Ang ACE2 KO, suggestive of remodeling. Results also showed enhanced oxidative stress in the myocardium and aorta of Ang ACE2 KO. There was a 3-fold elevation in macrophage inflammatory protein 1α (MIP 1α) in the aorta of ACE2 KO. Studies in the ACE2 KO model reveal the importance of ACE2 in the maladaptive cardiac and aortic responses to Ang II stimulation, seen as enhanced remodeling using physiological, structural, and biochemical markers. Results document a cardio- and vascular-protective role of ACE2 under pathological conditions.",
keywords = "aorta, cardiac dysfunction, echocardiography, oxidative stress, remodeling, renin-angiotensin system",
author = "Alghamri, {Mahmoud S.} and Weir, {Nathan M.} and Anstadt, {Mark P.} and Elased, {Khalid M.} and Susan Gurley and Mariana Morris",
year = "2013",
month = "3",
day = "1",
doi = "10.1177/1074248412460124",
language = "English (US)",
volume = "18",
pages = "138--151",
journal = "Journal of Cardiovascular Pharmacology and Therapeutics",
issn = "1074-2484",
publisher = "SAGE Publications Ltd",
number = "2",

}

TY - JOUR

T1 - Enhanced angiotensin II-induced cardiac and aortic remodeling in ACE2 knockout mice

AU - Alghamri, Mahmoud S.

AU - Weir, Nathan M.

AU - Anstadt, Mark P.

AU - Elased, Khalid M.

AU - Gurley, Susan

AU - Morris, Mariana

PY - 2013/3/1

Y1 - 2013/3/1

N2 - Angiotensin-converting enzyme 2 (ACE2) is present in the heart and thought to exert protective functions. We conducted studies in ACE2 deficient mice to determine whether enzyme loss would exacerbate the cardiac and vascular pathological responses to chronic subcutaneous (sc) angiotensin II (Ang II) infusion. Eight-week-old male ACE2 knockout (KO) and wild type (WT) mice were infused with Ang II (1000 ng/kg per min, 4 weeks) using mini-osmotic pumps. Blood pressure (radiotelemetry), cardiac function (echocardiography, echo), cardiac/aortic structure (histology, collagen, and oxidative stress), and vascular inflammation were examined. Before Ang II infusion, ACE2 KO mice showed unaltered cardiac function and blood pressure. After 4 weeks of Ang II infusion, the mean arterial pressure (MAP) increased from 96 ± 2 to 136 ± 17 mm Hg (∼40%) in WT and from 104 ± 5 to 141 ± 13 mm Hg (∼ 35%) in ACE2 KO. While there were no differences in MAP between groups, the ACE2 KO responded differently to the hypertensive stimulus. Echo analysis revealed severe myocardial dysfunction in Ang II-infused ACE2 KO (Ang ACE2 KO). Ejection fraction was lower (39% versus 50%) as was fractional shortening (27% versus 38%) in ACE2 KO versus WT, respectively. Cardiac dysfunction was associated with hypertrophic cardiomyopathy shown by increased left-ventricular wall thickness, average cardiomyocyte cross-sectional area, and heart weight/body weight ratio. Collagen staining in the myocardium and aorta revealed increased collagen in Ang ACE2 KO, suggestive of remodeling. Results also showed enhanced oxidative stress in the myocardium and aorta of Ang ACE2 KO. There was a 3-fold elevation in macrophage inflammatory protein 1α (MIP 1α) in the aorta of ACE2 KO. Studies in the ACE2 KO model reveal the importance of ACE2 in the maladaptive cardiac and aortic responses to Ang II stimulation, seen as enhanced remodeling using physiological, structural, and biochemical markers. Results document a cardio- and vascular-protective role of ACE2 under pathological conditions.

AB - Angiotensin-converting enzyme 2 (ACE2) is present in the heart and thought to exert protective functions. We conducted studies in ACE2 deficient mice to determine whether enzyme loss would exacerbate the cardiac and vascular pathological responses to chronic subcutaneous (sc) angiotensin II (Ang II) infusion. Eight-week-old male ACE2 knockout (KO) and wild type (WT) mice were infused with Ang II (1000 ng/kg per min, 4 weeks) using mini-osmotic pumps. Blood pressure (radiotelemetry), cardiac function (echocardiography, echo), cardiac/aortic structure (histology, collagen, and oxidative stress), and vascular inflammation were examined. Before Ang II infusion, ACE2 KO mice showed unaltered cardiac function and blood pressure. After 4 weeks of Ang II infusion, the mean arterial pressure (MAP) increased from 96 ± 2 to 136 ± 17 mm Hg (∼40%) in WT and from 104 ± 5 to 141 ± 13 mm Hg (∼ 35%) in ACE2 KO. While there were no differences in MAP between groups, the ACE2 KO responded differently to the hypertensive stimulus. Echo analysis revealed severe myocardial dysfunction in Ang II-infused ACE2 KO (Ang ACE2 KO). Ejection fraction was lower (39% versus 50%) as was fractional shortening (27% versus 38%) in ACE2 KO versus WT, respectively. Cardiac dysfunction was associated with hypertrophic cardiomyopathy shown by increased left-ventricular wall thickness, average cardiomyocyte cross-sectional area, and heart weight/body weight ratio. Collagen staining in the myocardium and aorta revealed increased collagen in Ang ACE2 KO, suggestive of remodeling. Results also showed enhanced oxidative stress in the myocardium and aorta of Ang ACE2 KO. There was a 3-fold elevation in macrophage inflammatory protein 1α (MIP 1α) in the aorta of ACE2 KO. Studies in the ACE2 KO model reveal the importance of ACE2 in the maladaptive cardiac and aortic responses to Ang II stimulation, seen as enhanced remodeling using physiological, structural, and biochemical markers. Results document a cardio- and vascular-protective role of ACE2 under pathological conditions.

KW - aorta

KW - cardiac dysfunction

KW - echocardiography

KW - oxidative stress

KW - remodeling

KW - renin-angiotensin system

UR - http://www.scopus.com/inward/record.url?scp=84873642707&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84873642707&partnerID=8YFLogxK

U2 - 10.1177/1074248412460124

DO - 10.1177/1074248412460124

M3 - Article

VL - 18

SP - 138

EP - 151

JO - Journal of Cardiovascular Pharmacology and Therapeutics

JF - Journal of Cardiovascular Pharmacology and Therapeutics

SN - 1074-2484

IS - 2

ER -