Endogenous endothelin-1 is required for cardiomyocyte survival in vivo

Xiao Song Zhao, Wentong Pan, Raffi Bekeredjian, Ralph V. Shohet

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

BACKGROUND - Endothelin-1 (ET-1) has potent vasoconstrictor and hypertrophic actions. Pharmacological antagonists of endothelin receptors attenuate cardiac hypertrophy, have been approved for treatment of pulmonary hypertension, and are under investigation for treatment of heart failure. To investigate the role of ET-1 in the heart, we created mice with cardiomyocyte deletion of ET-1. METHODS AND RESULTS - Mice with cardiomyocyte-specific deletion of ET-1 are phenotypically normal when young. Remarkably, as the mice age or when young animals are subjected to aortic banding, they develop an unexpected phenotype of progressive systolic dysfunction and cardiac dilation. Echocardiography, necropsy, histology, and molecular phenotype confirm a dilated cardiomyopathy. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling analysis reveals greater abundance of apoptotic nuclei in the ET-1-deficient hearts. Transcriptional and Western analyses suggest enhanced tumor necrosis factor (TNF)-mediated apoptosis with increases in caspase-8 activity. These ET-1-deficient hearts also have diminished nuclear factor (NF)-κB activity, resulting in diminution of downstream inhibitors of TNF signaling. CONCLUSIONS - Local ET-1 gene expression is necessary to maintain normal cardiac function and cardiomyocyte survival in mice with both age and hemodynamic stress. This cardiac-protective effect is mediated by paracrine ET-1 modulation of TNF-related apoptosis, in part through upregulation of NF-κB signaling.

Original languageEnglish (US)
Pages (from-to)830-837
Number of pages8
JournalCirculation
Volume114
Issue number8
DOIs
StatePublished - Aug 1 2006
Externally publishedYes

Fingerprint

Endothelin-1
Cardiac Myocytes
Tumor Necrosis Factor-alpha
Apoptosis
Phenotype
DNA Nucleotidylexotransferase
Caspase 8
Dilated Cardiomyopathy
Cardiomegaly
Vasoconstrictor Agents
Treatment Failure
Pulmonary Hypertension
Echocardiography
Dilatation
Histology
Up-Regulation
Heart Failure
Hemodynamics
Pharmacology
Gene Expression

Keywords

  • Apoptosis
  • Cardiomyopathy
  • Endothelin
  • Nuclear factor-kappa B
  • Tumor necrosis factor

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Endogenous endothelin-1 is required for cardiomyocyte survival in vivo. / Zhao, Xiao Song; Pan, Wentong; Bekeredjian, Raffi; Shohet, Ralph V.

In: Circulation, Vol. 114, No. 8, 01.08.2006, p. 830-837.

Research output: Contribution to journalArticle

Zhao, Xiao Song ; Pan, Wentong ; Bekeredjian, Raffi ; Shohet, Ralph V. / Endogenous endothelin-1 is required for cardiomyocyte survival in vivo. In: Circulation. 2006 ; Vol. 114, No. 8. pp. 830-837.
@article{f22bdf46e59c40bc88cf1663ab0dc505,
title = "Endogenous endothelin-1 is required for cardiomyocyte survival in vivo",
abstract = "BACKGROUND - Endothelin-1 (ET-1) has potent vasoconstrictor and hypertrophic actions. Pharmacological antagonists of endothelin receptors attenuate cardiac hypertrophy, have been approved for treatment of pulmonary hypertension, and are under investigation for treatment of heart failure. To investigate the role of ET-1 in the heart, we created mice with cardiomyocyte deletion of ET-1. METHODS AND RESULTS - Mice with cardiomyocyte-specific deletion of ET-1 are phenotypically normal when young. Remarkably, as the mice age or when young animals are subjected to aortic banding, they develop an unexpected phenotype of progressive systolic dysfunction and cardiac dilation. Echocardiography, necropsy, histology, and molecular phenotype confirm a dilated cardiomyopathy. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling analysis reveals greater abundance of apoptotic nuclei in the ET-1-deficient hearts. Transcriptional and Western analyses suggest enhanced tumor necrosis factor (TNF)-mediated apoptosis with increases in caspase-8 activity. These ET-1-deficient hearts also have diminished nuclear factor (NF)-κB activity, resulting in diminution of downstream inhibitors of TNF signaling. CONCLUSIONS - Local ET-1 gene expression is necessary to maintain normal cardiac function and cardiomyocyte survival in mice with both age and hemodynamic stress. This cardiac-protective effect is mediated by paracrine ET-1 modulation of TNF-related apoptosis, in part through upregulation of NF-κB signaling.",
keywords = "Apoptosis, Cardiomyopathy, Endothelin, Nuclear factor-kappa B, Tumor necrosis factor",
author = "Zhao, {Xiao Song} and Wentong Pan and Raffi Bekeredjian and Shohet, {Ralph V.}",
year = "2006",
month = "8",
day = "1",
doi = "10.1161/CIRCULATIONAHA.105.577288",
language = "English (US)",
volume = "114",
pages = "830--837",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "8",

}

TY - JOUR

T1 - Endogenous endothelin-1 is required for cardiomyocyte survival in vivo

AU - Zhao, Xiao Song

AU - Pan, Wentong

AU - Bekeredjian, Raffi

AU - Shohet, Ralph V.

PY - 2006/8/1

Y1 - 2006/8/1

N2 - BACKGROUND - Endothelin-1 (ET-1) has potent vasoconstrictor and hypertrophic actions. Pharmacological antagonists of endothelin receptors attenuate cardiac hypertrophy, have been approved for treatment of pulmonary hypertension, and are under investigation for treatment of heart failure. To investigate the role of ET-1 in the heart, we created mice with cardiomyocyte deletion of ET-1. METHODS AND RESULTS - Mice with cardiomyocyte-specific deletion of ET-1 are phenotypically normal when young. Remarkably, as the mice age or when young animals are subjected to aortic banding, they develop an unexpected phenotype of progressive systolic dysfunction and cardiac dilation. Echocardiography, necropsy, histology, and molecular phenotype confirm a dilated cardiomyopathy. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling analysis reveals greater abundance of apoptotic nuclei in the ET-1-deficient hearts. Transcriptional and Western analyses suggest enhanced tumor necrosis factor (TNF)-mediated apoptosis with increases in caspase-8 activity. These ET-1-deficient hearts also have diminished nuclear factor (NF)-κB activity, resulting in diminution of downstream inhibitors of TNF signaling. CONCLUSIONS - Local ET-1 gene expression is necessary to maintain normal cardiac function and cardiomyocyte survival in mice with both age and hemodynamic stress. This cardiac-protective effect is mediated by paracrine ET-1 modulation of TNF-related apoptosis, in part through upregulation of NF-κB signaling.

AB - BACKGROUND - Endothelin-1 (ET-1) has potent vasoconstrictor and hypertrophic actions. Pharmacological antagonists of endothelin receptors attenuate cardiac hypertrophy, have been approved for treatment of pulmonary hypertension, and are under investigation for treatment of heart failure. To investigate the role of ET-1 in the heart, we created mice with cardiomyocyte deletion of ET-1. METHODS AND RESULTS - Mice with cardiomyocyte-specific deletion of ET-1 are phenotypically normal when young. Remarkably, as the mice age or when young animals are subjected to aortic banding, they develop an unexpected phenotype of progressive systolic dysfunction and cardiac dilation. Echocardiography, necropsy, histology, and molecular phenotype confirm a dilated cardiomyopathy. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling analysis reveals greater abundance of apoptotic nuclei in the ET-1-deficient hearts. Transcriptional and Western analyses suggest enhanced tumor necrosis factor (TNF)-mediated apoptosis with increases in caspase-8 activity. These ET-1-deficient hearts also have diminished nuclear factor (NF)-κB activity, resulting in diminution of downstream inhibitors of TNF signaling. CONCLUSIONS - Local ET-1 gene expression is necessary to maintain normal cardiac function and cardiomyocyte survival in mice with both age and hemodynamic stress. This cardiac-protective effect is mediated by paracrine ET-1 modulation of TNF-related apoptosis, in part through upregulation of NF-κB signaling.

KW - Apoptosis

KW - Cardiomyopathy

KW - Endothelin

KW - Nuclear factor-kappa B

KW - Tumor necrosis factor

UR - http://www.scopus.com/inward/record.url?scp=33747594735&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33747594735&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.105.577288

DO - 10.1161/CIRCULATIONAHA.105.577288

M3 - Article

VL - 114

SP - 830

EP - 837

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 8

ER -