Endothelial expression of hypoxia-inducible factor 1 protects the murine heart and aorta from pressure overload by suppression of TGF-β signaling

Hong Wei, Djahida Bedja, Norimichi Koitabashi, Dongmei Xing, Jasper Chen, Karen Fox-Talbot, Rosanne Rouf, Shaoping Chen, Charles Jr Steenbergen, John Harmon, Harry C Dietz, Kathleen L Gabrielson, David A Kass, Gregg L Semenza

Research output: Contribution to journalArticle

Abstract

Chronic systemic hypertension causes cardiac pressure overload leading to increased myocardial O 2 consumption. Hypoxia-inducible factor 1 (HIF-1) is a master regulator of O 2 homeostasis. Mouse embryos lacking expression of the O 2-regulated HIF-1α subunit die at midgestation with severe cardiac malformations and vascular regression. Here we report that Hif1a f/f;Tie2-Cre conditional knockout mice, which lack HIF-1α expression only in Tie2 + lineage cells, develop normally, but when subjected to pressure overload induced by transaortic constriction (TAC), they manifest rapid cardiac decompensation, which is accompanied by excess cardiac fibrosis and myocardial hypertrophy, decreased myocardial capillary density, increased myocardial hypoxia and apoptosis, and increased TGF-β signaling through both canonical and noncanonical pathways that activate SMAD2/3 and ERK1/2, respectively, within endothelial cells of cardiac blood vessels. TAC also induces dilatation of the proximal aorta through enhanced TGF-β signaling in Hif1a f/f; Tie2-Cre mice. Inhibition of TGF-β signaling by treatment with neutralizing antibody or pharmacologic inhibition of MEK-ERK signaling prevented TAC-induced contractile dysfunction and pathological remodeling. Thus, HIF-1 plays a critical protective role in the adaptation of the heart and aorta to pressure overload by negatively regulating TGF-β signaling in endothelial cells. Treatment of wild-type mice with digoxin, which inhibits HIF-1α synthesis, resulted in rapid cardiac failure after TAC. Although digoxin has been used for decades as an inotropic agent to treat heart failure, it does not improve survival, suggesting that the countertherapeutic effects of digoxin observed in the TAC mouse model may have clinical relevance.

Original languageEnglish (US)
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number14
DOIs
StatePublished - Apr 3 2012

Fingerprint

Hypoxia-Inducible Factor 1
Constriction
Aorta
Digoxin
Pressure
Endothelial Cells
Heart Failure
Vascular Malformations
Mitogen-Activated Protein Kinase Kinases
Neutralizing Antibodies
Knockout Mice
Hypertrophy
Blood Vessels
Dilatation
Homeostasis
Fibrosis
Embryonic Structures
Apoptosis
Hypertension

Keywords

  • Aortic root dilatation
  • Congestive heart failure
  • Endothelium

ASJC Scopus subject areas

  • General

Cite this

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title = "Endothelial expression of hypoxia-inducible factor 1 protects the murine heart and aorta from pressure overload by suppression of TGF-β signaling",
abstract = "Chronic systemic hypertension causes cardiac pressure overload leading to increased myocardial O 2 consumption. Hypoxia-inducible factor 1 (HIF-1) is a master regulator of O 2 homeostasis. Mouse embryos lacking expression of the O 2-regulated HIF-1α subunit die at midgestation with severe cardiac malformations and vascular regression. Here we report that Hif1a f/f;Tie2-Cre conditional knockout mice, which lack HIF-1α expression only in Tie2 + lineage cells, develop normally, but when subjected to pressure overload induced by transaortic constriction (TAC), they manifest rapid cardiac decompensation, which is accompanied by excess cardiac fibrosis and myocardial hypertrophy, decreased myocardial capillary density, increased myocardial hypoxia and apoptosis, and increased TGF-β signaling through both canonical and noncanonical pathways that activate SMAD2/3 and ERK1/2, respectively, within endothelial cells of cardiac blood vessels. TAC also induces dilatation of the proximal aorta through enhanced TGF-β signaling in Hif1a f/f; Tie2-Cre mice. Inhibition of TGF-β signaling by treatment with neutralizing antibody or pharmacologic inhibition of MEK-ERK signaling prevented TAC-induced contractile dysfunction and pathological remodeling. Thus, HIF-1 plays a critical protective role in the adaptation of the heart and aorta to pressure overload by negatively regulating TGF-β signaling in endothelial cells. Treatment of wild-type mice with digoxin, which inhibits HIF-1α synthesis, resulted in rapid cardiac failure after TAC. Although digoxin has been used for decades as an inotropic agent to treat heart failure, it does not improve survival, suggesting that the countertherapeutic effects of digoxin observed in the TAC mouse model may have clinical relevance.",
keywords = "Aortic root dilatation, Congestive heart failure, Endothelium",
author = "Hong Wei and Djahida Bedja and Norimichi Koitabashi and Dongmei Xing and Jasper Chen and Karen Fox-Talbot and Rosanne Rouf and Shaoping Chen and Steenbergen, {Charles Jr} and John Harmon and Dietz, {Harry C} and Gabrielson, {Kathleen L} and Kass, {David A} and Semenza, {Gregg L}",
year = "2012",
month = "4",
day = "3",
doi = "10.1073/pnas.1202081109",
language = "English (US)",
volume = "109",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
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TY - JOUR

T1 - Endothelial expression of hypoxia-inducible factor 1 protects the murine heart and aorta from pressure overload by suppression of TGF-β signaling

AU - Wei, Hong

AU - Bedja, Djahida

AU - Koitabashi, Norimichi

AU - Xing, Dongmei

AU - Chen, Jasper

AU - Fox-Talbot, Karen

AU - Rouf, Rosanne

AU - Chen, Shaoping

AU - Steenbergen, Charles Jr

AU - Harmon, John

AU - Dietz, Harry C

AU - Gabrielson, Kathleen L

AU - Kass, David A

AU - Semenza, Gregg L

PY - 2012/4/3

Y1 - 2012/4/3

N2 - Chronic systemic hypertension causes cardiac pressure overload leading to increased myocardial O 2 consumption. Hypoxia-inducible factor 1 (HIF-1) is a master regulator of O 2 homeostasis. Mouse embryos lacking expression of the O 2-regulated HIF-1α subunit die at midgestation with severe cardiac malformations and vascular regression. Here we report that Hif1a f/f;Tie2-Cre conditional knockout mice, which lack HIF-1α expression only in Tie2 + lineage cells, develop normally, but when subjected to pressure overload induced by transaortic constriction (TAC), they manifest rapid cardiac decompensation, which is accompanied by excess cardiac fibrosis and myocardial hypertrophy, decreased myocardial capillary density, increased myocardial hypoxia and apoptosis, and increased TGF-β signaling through both canonical and noncanonical pathways that activate SMAD2/3 and ERK1/2, respectively, within endothelial cells of cardiac blood vessels. TAC also induces dilatation of the proximal aorta through enhanced TGF-β signaling in Hif1a f/f; Tie2-Cre mice. Inhibition of TGF-β signaling by treatment with neutralizing antibody or pharmacologic inhibition of MEK-ERK signaling prevented TAC-induced contractile dysfunction and pathological remodeling. Thus, HIF-1 plays a critical protective role in the adaptation of the heart and aorta to pressure overload by negatively regulating TGF-β signaling in endothelial cells. Treatment of wild-type mice with digoxin, which inhibits HIF-1α synthesis, resulted in rapid cardiac failure after TAC. Although digoxin has been used for decades as an inotropic agent to treat heart failure, it does not improve survival, suggesting that the countertherapeutic effects of digoxin observed in the TAC mouse model may have clinical relevance.

AB - Chronic systemic hypertension causes cardiac pressure overload leading to increased myocardial O 2 consumption. Hypoxia-inducible factor 1 (HIF-1) is a master regulator of O 2 homeostasis. Mouse embryos lacking expression of the O 2-regulated HIF-1α subunit die at midgestation with severe cardiac malformations and vascular regression. Here we report that Hif1a f/f;Tie2-Cre conditional knockout mice, which lack HIF-1α expression only in Tie2 + lineage cells, develop normally, but when subjected to pressure overload induced by transaortic constriction (TAC), they manifest rapid cardiac decompensation, which is accompanied by excess cardiac fibrosis and myocardial hypertrophy, decreased myocardial capillary density, increased myocardial hypoxia and apoptosis, and increased TGF-β signaling through both canonical and noncanonical pathways that activate SMAD2/3 and ERK1/2, respectively, within endothelial cells of cardiac blood vessels. TAC also induces dilatation of the proximal aorta through enhanced TGF-β signaling in Hif1a f/f; Tie2-Cre mice. Inhibition of TGF-β signaling by treatment with neutralizing antibody or pharmacologic inhibition of MEK-ERK signaling prevented TAC-induced contractile dysfunction and pathological remodeling. Thus, HIF-1 plays a critical protective role in the adaptation of the heart and aorta to pressure overload by negatively regulating TGF-β signaling in endothelial cells. Treatment of wild-type mice with digoxin, which inhibits HIF-1α synthesis, resulted in rapid cardiac failure after TAC. Although digoxin has been used for decades as an inotropic agent to treat heart failure, it does not improve survival, suggesting that the countertherapeutic effects of digoxin observed in the TAC mouse model may have clinical relevance.

KW - Aortic root dilatation

KW - Congestive heart failure

KW - Endothelium

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U2 - 10.1073/pnas.1202081109

DO - 10.1073/pnas.1202081109

M3 - Article

VL - 109

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

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