Induction and functional significance of the heme oxygenase system in pathological shear stress in vivo

Lu Kang, Matthew L. Hillestad, Joseph Peter Grande, Anthony J. Croatt, Michael A Barry, Gianrico Farrugia, Zvonimir S Katusic, Karl A Nath

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Abstract

The present study examined the heme oxygenase (HO) system in an in vivo murine model of pathological shear stress induced by partial carotid artery ligation. In this model, along with upregulation of vasculopathic genes, HO-1 is induced in the endothelium and adventitia, whereas HO-2 is mainly upregulated in the endothelium. Within minutes of ligation, NF-κB, a transcription factor that upregulates vasculopathic genes and HO-1, is activated. Failure to express either HO-1 or HO-2 exaggerates the reduction in carotid blood flow and exacerbates vascular injury. After artery ligation, comparable induction of HO-2 occurred in HO-1<sup>+/+</sup> and HO-1<sup>-/-</sup> mice, whereas HO-1 induction was exaggerated in HO-2<sup>+/+</sup> mice compared with HO-2<sup>-/-</sup> mice. Upregulation of HO-1 by an adeno-associated viral vector increased vascular HO-1 expression and HO activity and augmented blood flow in both ligated and contralateral carotid arteries. Acute inhibition of HO activity decreased flow in the ligated carotid artery, whereas a product of HO, carbon monoxide (CO), delivered by CO-releasing molecule-3, increased carotid blood flow. In conclusion, in the partial carotid artery ligation model of pathological shear stress, this study provides the first demonstration of 1) upregulation and vasoprotective effects of HO-1 and HO-2 and the vasorelaxant effects of CO as well as 2) vascular upregulation of HO-1 in vivo by an adeno-associated viral vector that is attended by a salutary vascular response. Induction of HO-1 may reside in NF-κB activation, and, along with induced HO-2, such upregulation of HO-1 provides a countervailing vasoprotective response in pathological shear stress in vivo.

Original languageEnglish (US)
Pages (from-to)H1402-H1413
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume308
Issue number11
DOIs
StatePublished - Jun 1 2015

Fingerprint

Heme Oxygenase (Decyclizing)
Heme Oxygenase-1
Up-Regulation
Carotid Arteries
Ligation
Carbon Monoxide
Blood Vessels
Endothelium
Adventitia
Vascular System Injuries
heme oxygenase-2
Vasodilator Agents
Genes
Transcription Factors

Keywords

  • Cytokines
  • Heme oxygenase
  • Inflammation
  • Shear stress
  • Vascular injury

ASJC Scopus subject areas

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

Cite this

@article{099ea9dfdcfa457ca543ef6322940380,
title = "Induction and functional significance of the heme oxygenase system in pathological shear stress in vivo",
abstract = "The present study examined the heme oxygenase (HO) system in an in vivo murine model of pathological shear stress induced by partial carotid artery ligation. In this model, along with upregulation of vasculopathic genes, HO-1 is induced in the endothelium and adventitia, whereas HO-2 is mainly upregulated in the endothelium. Within minutes of ligation, NF-κB, a transcription factor that upregulates vasculopathic genes and HO-1, is activated. Failure to express either HO-1 or HO-2 exaggerates the reduction in carotid blood flow and exacerbates vascular injury. After artery ligation, comparable induction of HO-2 occurred in HO-1+/+ and HO-1-/- mice, whereas HO-1 induction was exaggerated in HO-2+/+ mice compared with HO-2-/- mice. Upregulation of HO-1 by an adeno-associated viral vector increased vascular HO-1 expression and HO activity and augmented blood flow in both ligated and contralateral carotid arteries. Acute inhibition of HO activity decreased flow in the ligated carotid artery, whereas a product of HO, carbon monoxide (CO), delivered by CO-releasing molecule-3, increased carotid blood flow. In conclusion, in the partial carotid artery ligation model of pathological shear stress, this study provides the first demonstration of 1) upregulation and vasoprotective effects of HO-1 and HO-2 and the vasorelaxant effects of CO as well as 2) vascular upregulation of HO-1 in vivo by an adeno-associated viral vector that is attended by a salutary vascular response. Induction of HO-1 may reside in NF-κB activation, and, along with induced HO-2, such upregulation of HO-1 provides a countervailing vasoprotective response in pathological shear stress in vivo.",
keywords = "Cytokines, Heme oxygenase, Inflammation, Shear stress, Vascular injury",
author = "Lu Kang and Hillestad, {Matthew L.} and Grande, {Joseph Peter} and Croatt, {Anthony J.} and Barry, {Michael A} and Gianrico Farrugia and Katusic, {Zvonimir S} and Nath, {Karl A}",
year = "2015",
month = "6",
day = "1",
doi = "10.1152/ajpheart.00882.2014",
language = "English (US)",
volume = "308",
pages = "H1402--H1413",
journal = "American Journal of Physiology - Renal Fluid and Electrolyte Physiology",
issn = "1931-857X",
publisher = "American Physiological Society",
number = "11",

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TY - JOUR

T1 - Induction and functional significance of the heme oxygenase system in pathological shear stress in vivo

AU - Kang, Lu

AU - Hillestad, Matthew L.

AU - Grande, Joseph Peter

AU - Croatt, Anthony J.

AU - Barry, Michael A

AU - Farrugia, Gianrico

AU - Katusic, Zvonimir S

AU - Nath, Karl A

PY - 2015/6/1

Y1 - 2015/6/1

N2 - The present study examined the heme oxygenase (HO) system in an in vivo murine model of pathological shear stress induced by partial carotid artery ligation. In this model, along with upregulation of vasculopathic genes, HO-1 is induced in the endothelium and adventitia, whereas HO-2 is mainly upregulated in the endothelium. Within minutes of ligation, NF-κB, a transcription factor that upregulates vasculopathic genes and HO-1, is activated. Failure to express either HO-1 or HO-2 exaggerates the reduction in carotid blood flow and exacerbates vascular injury. After artery ligation, comparable induction of HO-2 occurred in HO-1+/+ and HO-1-/- mice, whereas HO-1 induction was exaggerated in HO-2+/+ mice compared with HO-2-/- mice. Upregulation of HO-1 by an adeno-associated viral vector increased vascular HO-1 expression and HO activity and augmented blood flow in both ligated and contralateral carotid arteries. Acute inhibition of HO activity decreased flow in the ligated carotid artery, whereas a product of HO, carbon monoxide (CO), delivered by CO-releasing molecule-3, increased carotid blood flow. In conclusion, in the partial carotid artery ligation model of pathological shear stress, this study provides the first demonstration of 1) upregulation and vasoprotective effects of HO-1 and HO-2 and the vasorelaxant effects of CO as well as 2) vascular upregulation of HO-1 in vivo by an adeno-associated viral vector that is attended by a salutary vascular response. Induction of HO-1 may reside in NF-κB activation, and, along with induced HO-2, such upregulation of HO-1 provides a countervailing vasoprotective response in pathological shear stress in vivo.

AB - The present study examined the heme oxygenase (HO) system in an in vivo murine model of pathological shear stress induced by partial carotid artery ligation. In this model, along with upregulation of vasculopathic genes, HO-1 is induced in the endothelium and adventitia, whereas HO-2 is mainly upregulated in the endothelium. Within minutes of ligation, NF-κB, a transcription factor that upregulates vasculopathic genes and HO-1, is activated. Failure to express either HO-1 or HO-2 exaggerates the reduction in carotid blood flow and exacerbates vascular injury. After artery ligation, comparable induction of HO-2 occurred in HO-1+/+ and HO-1-/- mice, whereas HO-1 induction was exaggerated in HO-2+/+ mice compared with HO-2-/- mice. Upregulation of HO-1 by an adeno-associated viral vector increased vascular HO-1 expression and HO activity and augmented blood flow in both ligated and contralateral carotid arteries. Acute inhibition of HO activity decreased flow in the ligated carotid artery, whereas a product of HO, carbon monoxide (CO), delivered by CO-releasing molecule-3, increased carotid blood flow. In conclusion, in the partial carotid artery ligation model of pathological shear stress, this study provides the first demonstration of 1) upregulation and vasoprotective effects of HO-1 and HO-2 and the vasorelaxant effects of CO as well as 2) vascular upregulation of HO-1 in vivo by an adeno-associated viral vector that is attended by a salutary vascular response. Induction of HO-1 may reside in NF-κB activation, and, along with induced HO-2, such upregulation of HO-1 provides a countervailing vasoprotective response in pathological shear stress in vivo.

KW - Cytokines

KW - Heme oxygenase

KW - Inflammation

KW - Shear stress

KW - Vascular injury

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U2 - 10.1152/ajpheart.00882.2014

DO - 10.1152/ajpheart.00882.2014

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SP - H1402-H1413

JO - American Journal of Physiology - Renal Fluid and Electrolyte Physiology

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SN - 1931-857X

IS - 11

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