Hypoxia-Inducible Factor 1α Is a Critical Downstream Mediator for Hypoxia-Induced Mitogenic Factor (FIZZ1/RELMα)-Induced Pulmonary Hypertension

Roger A. Johns, Eiki Takimoto, Lucas W. Meuchel, Esra Elsaigh, Ailan Zhang, Nicola M. Heller, Gregg L. Semenza, Kazuyo Yamaji-Kegan

Research output: Research - peer-reviewArticle

Abstract

Objective-Pulmonary hypertension (PH) is characterized by progressive elevation of pulmonary vascular resistance, right ventricular failure, and ultimately death. We have shown that in rodents, hypoxia-induced mitogenic factor (HIMF; also known as FIZZ1 or resistin-like molecule-β) causes PH by initiating lung vascular inflammation. We hypothesized that hypoxia-inducible factor-1 (HIF-1) is a critical downstream signal mediator of HIMF during PH development. Approach and Results-In this study, we compared the degree of HIMF-induced pulmonary vascular remodeling and PH development in wild-type (HIF-1α+/+) and HIF-1α heterozygous null (HIF-1α+/-) mice. HIMF-induced PH was significantly diminished in HIF-1α+/- mice and was accompanied by a dysregulated vascular endothelial growth factor-A-vascular endothelial growth factor receptor 2 pathway. HIF-1α was critical for bone marrow-derived cell migration and vascular tube formation in response to HIMF. Furthermore, HIMF and its human homolog, resistin-like molecule-β, significantly increased interleukin (IL)-6 in macrophages and lung resident cells through a mechanism dependent on HIF-1α and, at least to some extent, on nuclear factor κB. Conclusions-Our results suggest that HIF-1α is a critical downstream transcription factor for HIMF-induced pulmonary vascular remodeling and PH development. Importantly, both HIMF and human resistin-like molecule-β significantly increased IL-6 in lung resident cells and increased perivascular accumulation of IL-6-expressing macrophages in the lungs of mice. These data suggest that HIMF can induce HIF-1, vascular endothelial growth factor-A, and interleukin-6, which are critical mediators of both hypoxic inflammation and PH pathophysiology.

LanguageEnglish (US)
Pages134-144
Number of pages11
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume36
Issue number1
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

Fingerprint

Pulmonary Hypertension
Hypoxia
Lung
Interleukin-6
Hypoxia-Inducible Factor 1
Vascular Endothelial Growth Factor A
Blood Vessels
Macrophages
Vascular Remodeling
Resistin
Vascular Endothelial Growth Factor Receptor-2
Bone Marrow Cells
Vascular Resistance
Cell Movement
Rodentia
Pneumonia
Transcription Factors
Inflammation
human RETN protein
human RETNLB protein

Keywords

  • hypertension
  • hypoxia-inducible factor 1
  • interleukins
  • macrophages
  • pulmonary
  • resistin-like molecule

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

@article{149a78c16bd84da8b2fb3f9337e310c1,
title = "Hypoxia-Inducible Factor 1α Is a Critical Downstream Mediator for Hypoxia-Induced Mitogenic Factor (FIZZ1/RELMα)-Induced Pulmonary Hypertension",
abstract = "Objective-Pulmonary hypertension (PH) is characterized by progressive elevation of pulmonary vascular resistance, right ventricular failure, and ultimately death. We have shown that in rodents, hypoxia-induced mitogenic factor (HIMF; also known as FIZZ1 or resistin-like molecule-β) causes PH by initiating lung vascular inflammation. We hypothesized that hypoxia-inducible factor-1 (HIF-1) is a critical downstream signal mediator of HIMF during PH development. Approach and Results-In this study, we compared the degree of HIMF-induced pulmonary vascular remodeling and PH development in wild-type (HIF-1α+/+) and HIF-1α heterozygous null (HIF-1α+/-) mice. HIMF-induced PH was significantly diminished in HIF-1α+/- mice and was accompanied by a dysregulated vascular endothelial growth factor-A-vascular endothelial growth factor receptor 2 pathway. HIF-1α was critical for bone marrow-derived cell migration and vascular tube formation in response to HIMF. Furthermore, HIMF and its human homolog, resistin-like molecule-β, significantly increased interleukin (IL)-6 in macrophages and lung resident cells through a mechanism dependent on HIF-1α and, at least to some extent, on nuclear factor κB. Conclusions-Our results suggest that HIF-1α is a critical downstream transcription factor for HIMF-induced pulmonary vascular remodeling and PH development. Importantly, both HIMF and human resistin-like molecule-β significantly increased IL-6 in lung resident cells and increased perivascular accumulation of IL-6-expressing macrophages in the lungs of mice. These data suggest that HIMF can induce HIF-1, vascular endothelial growth factor-A, and interleukin-6, which are critical mediators of both hypoxic inflammation and PH pathophysiology.",
keywords = "hypertension, hypoxia-inducible factor 1, interleukins, macrophages, pulmonary, resistin-like molecule",
author = "Johns, {Roger A.} and Eiki Takimoto and Meuchel, {Lucas W.} and Esra Elsaigh and Ailan Zhang and Heller, {Nicola M.} and Semenza, {Gregg L.} and Kazuyo Yamaji-Kegan",
year = "2016",
month = "1",
doi = "10.1161/ATVBAHA.115.306710",
volume = "36",
pages = "134--144",
journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",
issn = "1079-5642",
publisher = "Lippincott Williams and Wilkins",
number = "1",

}

TY - JOUR

T1 - Hypoxia-Inducible Factor 1α Is a Critical Downstream Mediator for Hypoxia-Induced Mitogenic Factor (FIZZ1/RELMα)-Induced Pulmonary Hypertension

AU - Johns,Roger A.

AU - Takimoto,Eiki

AU - Meuchel,Lucas W.

AU - Elsaigh,Esra

AU - Zhang,Ailan

AU - Heller,Nicola M.

AU - Semenza,Gregg L.

AU - Yamaji-Kegan,Kazuyo

PY - 2016/1/1

Y1 - 2016/1/1

N2 - Objective-Pulmonary hypertension (PH) is characterized by progressive elevation of pulmonary vascular resistance, right ventricular failure, and ultimately death. We have shown that in rodents, hypoxia-induced mitogenic factor (HIMF; also known as FIZZ1 or resistin-like molecule-β) causes PH by initiating lung vascular inflammation. We hypothesized that hypoxia-inducible factor-1 (HIF-1) is a critical downstream signal mediator of HIMF during PH development. Approach and Results-In this study, we compared the degree of HIMF-induced pulmonary vascular remodeling and PH development in wild-type (HIF-1α+/+) and HIF-1α heterozygous null (HIF-1α+/-) mice. HIMF-induced PH was significantly diminished in HIF-1α+/- mice and was accompanied by a dysregulated vascular endothelial growth factor-A-vascular endothelial growth factor receptor 2 pathway. HIF-1α was critical for bone marrow-derived cell migration and vascular tube formation in response to HIMF. Furthermore, HIMF and its human homolog, resistin-like molecule-β, significantly increased interleukin (IL)-6 in macrophages and lung resident cells through a mechanism dependent on HIF-1α and, at least to some extent, on nuclear factor κB. Conclusions-Our results suggest that HIF-1α is a critical downstream transcription factor for HIMF-induced pulmonary vascular remodeling and PH development. Importantly, both HIMF and human resistin-like molecule-β significantly increased IL-6 in lung resident cells and increased perivascular accumulation of IL-6-expressing macrophages in the lungs of mice. These data suggest that HIMF can induce HIF-1, vascular endothelial growth factor-A, and interleukin-6, which are critical mediators of both hypoxic inflammation and PH pathophysiology.

AB - Objective-Pulmonary hypertension (PH) is characterized by progressive elevation of pulmonary vascular resistance, right ventricular failure, and ultimately death. We have shown that in rodents, hypoxia-induced mitogenic factor (HIMF; also known as FIZZ1 or resistin-like molecule-β) causes PH by initiating lung vascular inflammation. We hypothesized that hypoxia-inducible factor-1 (HIF-1) is a critical downstream signal mediator of HIMF during PH development. Approach and Results-In this study, we compared the degree of HIMF-induced pulmonary vascular remodeling and PH development in wild-type (HIF-1α+/+) and HIF-1α heterozygous null (HIF-1α+/-) mice. HIMF-induced PH was significantly diminished in HIF-1α+/- mice and was accompanied by a dysregulated vascular endothelial growth factor-A-vascular endothelial growth factor receptor 2 pathway. HIF-1α was critical for bone marrow-derived cell migration and vascular tube formation in response to HIMF. Furthermore, HIMF and its human homolog, resistin-like molecule-β, significantly increased interleukin (IL)-6 in macrophages and lung resident cells through a mechanism dependent on HIF-1α and, at least to some extent, on nuclear factor κB. Conclusions-Our results suggest that HIF-1α is a critical downstream transcription factor for HIMF-induced pulmonary vascular remodeling and PH development. Importantly, both HIMF and human resistin-like molecule-β significantly increased IL-6 in lung resident cells and increased perivascular accumulation of IL-6-expressing macrophages in the lungs of mice. These data suggest that HIMF can induce HIF-1, vascular endothelial growth factor-A, and interleukin-6, which are critical mediators of both hypoxic inflammation and PH pathophysiology.

KW - hypertension

KW - hypoxia-inducible factor 1

KW - interleukins

KW - macrophages

KW - pulmonary

KW - resistin-like molecule

UR - http://www.scopus.com/inward/record.url?scp=84952639617&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84952639617&partnerID=8YFLogxK

U2 - 10.1161/ATVBAHA.115.306710

DO - 10.1161/ATVBAHA.115.306710

M3 - Article

VL - 36

SP - 134

EP - 144

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

T2 - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

SN - 1079-5642

IS - 1

ER -