The role of NADPH oxidase in chronic intermittent hypoxia-induced pulmonary hypertension in mice

Rachel E. Nisbet, Anitra S. Graves, Dean J. Kleinhenz, Heidi L. Rupnow, Alana L. Reed, Tai-Hwang Fan, Patrick O. Mitchell, Roy L. Sutliff, C. Michael Hart

Research output: Contribution to journalArticle

95 Citations (Scopus)

Abstract

Obstructive sleep apnea, characterized by intermittent periods of hypoxemia, is an independent risk factor for the development of pulmonary hypertension. However, the exact mechanisms of this disorder remain to be defined. Enhanced NADP Hoxidase expression and superoxide (O2 -·) generation in the pulmonary vasculature play a critical role in hypoxia-induced pulmonary hypertension. Therefore, the current study explores the hypothesis that chronic intermittent hypoxia (CIH) causes pulmonary hypertension, in part, by increasing NADPH oxidase-derived reactive oxygen species (ROS) that contribute to pulmonary vascular remodeling and hypertension. To test this hypothesis, male C57Bl/6 mice and gp91phox knockout mice were exposed to CIH for 8 hours per day, 5 days per week for 8 weeks. CIH mice were placed in a chamber where the oxygen concentration was cycled between 21% and 10% O2 45 times per hour. Exposure to CIH for 8 weeks increased right ventricular systolic pressure (RVSP), right ventricle (RV):left ventricle (LV) + septum (S) weight ratio, an index of RV hypertrophy, and thickness of the right ventricular anterior wall as measured by echocardiography. CIH exposure also caused pulmonary vascular remodeling as demonstrated by increased muscularization of the distal pulmonary vasculature. CIH-induced pulmonary hypertension was associated with increased lung levels of the NADPH oxidase subunits, Nox4 and p22phox, as well as increased activity of platelet-derived growth factor receptor β and its associated downstream effector, Akt kinase. These CIH-induced derangements were attenuated in similarly treated gp91phox knockout mice. These findings demonstrate that NADPH oxidase-derived ROS contribute to the development of pulmonary vascular remodeling and hypertension caused by CIH.

Original languageEnglish (US)
Pages (from-to)601-609
Number of pages9
JournalAmerican journal of respiratory cell and molecular biology
Volume40
Issue number5
DOIs
StatePublished - May 1 2009

Fingerprint

NADPH Oxidase
Pulmonary Hypertension
Reactive Oxygen Species
Echocardiography
Platelet-Derived Growth Factor Receptors
Lung
NADP
Superoxides
Heart Ventricles
Phosphotransferases
Oxygen
Knockout Mice
Hypoxia
Hypertension
Right Ventricular Hypertrophy
Obstructive Sleep Apnea
Ventricular Pressure
Blood Pressure
Weights and Measures

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

The role of NADPH oxidase in chronic intermittent hypoxia-induced pulmonary hypertension in mice. / Nisbet, Rachel E.; Graves, Anitra S.; Kleinhenz, Dean J.; Rupnow, Heidi L.; Reed, Alana L.; Fan, Tai-Hwang; Mitchell, Patrick O.; Sutliff, Roy L.; Michael Hart, C.

In: American journal of respiratory cell and molecular biology, Vol. 40, No. 5, 01.05.2009, p. 601-609.

Research output: Contribution to journalArticle

Nisbet, RE, Graves, AS, Kleinhenz, DJ, Rupnow, HL, Reed, AL, Fan, T-H, Mitchell, PO, Sutliff, RL & Michael Hart, C 2009, 'The role of NADPH oxidase in chronic intermittent hypoxia-induced pulmonary hypertension in mice', American journal of respiratory cell and molecular biology, vol. 40, no. 5, pp. 601-609. https://doi.org/10.1165/2008-0145OC
Nisbet, Rachel E. ; Graves, Anitra S. ; Kleinhenz, Dean J. ; Rupnow, Heidi L. ; Reed, Alana L. ; Fan, Tai-Hwang ; Mitchell, Patrick O. ; Sutliff, Roy L. ; Michael Hart, C. / The role of NADPH oxidase in chronic intermittent hypoxia-induced pulmonary hypertension in mice. In: American journal of respiratory cell and molecular biology. 2009 ; Vol. 40, No. 5. pp. 601-609.
@article{4945114855dd44c8b1b8efb4e07861fa,
title = "The role of NADPH oxidase in chronic intermittent hypoxia-induced pulmonary hypertension in mice",
abstract = "Obstructive sleep apnea, characterized by intermittent periods of hypoxemia, is an independent risk factor for the development of pulmonary hypertension. However, the exact mechanisms of this disorder remain to be defined. Enhanced NADP Hoxidase expression and superoxide (O2 -·) generation in the pulmonary vasculature play a critical role in hypoxia-induced pulmonary hypertension. Therefore, the current study explores the hypothesis that chronic intermittent hypoxia (CIH) causes pulmonary hypertension, in part, by increasing NADPH oxidase-derived reactive oxygen species (ROS) that contribute to pulmonary vascular remodeling and hypertension. To test this hypothesis, male C57Bl/6 mice and gp91phox knockout mice were exposed to CIH for 8 hours per day, 5 days per week for 8 weeks. CIH mice were placed in a chamber where the oxygen concentration was cycled between 21{\%} and 10{\%} O2 45 times per hour. Exposure to CIH for 8 weeks increased right ventricular systolic pressure (RVSP), right ventricle (RV):left ventricle (LV) + septum (S) weight ratio, an index of RV hypertrophy, and thickness of the right ventricular anterior wall as measured by echocardiography. CIH exposure also caused pulmonary vascular remodeling as demonstrated by increased muscularization of the distal pulmonary vasculature. CIH-induced pulmonary hypertension was associated with increased lung levels of the NADPH oxidase subunits, Nox4 and p22phox, as well as increased activity of platelet-derived growth factor receptor β and its associated downstream effector, Akt kinase. These CIH-induced derangements were attenuated in similarly treated gp91phox knockout mice. These findings demonstrate that NADPH oxidase-derived ROS contribute to the development of pulmonary vascular remodeling and hypertension caused by CIH.",
author = "Nisbet, {Rachel E.} and Graves, {Anitra S.} and Kleinhenz, {Dean J.} and Rupnow, {Heidi L.} and Reed, {Alana L.} and Tai-Hwang Fan and Mitchell, {Patrick O.} and Sutliff, {Roy L.} and {Michael Hart}, C.",
year = "2009",
month = "5",
day = "1",
doi = "10.1165/2008-0145OC",
language = "English (US)",
volume = "40",
pages = "601--609",
journal = "American Journal of Respiratory Cell and Molecular Biology",
issn = "1044-1549",
publisher = "American Thoracic Society",
number = "5",

}

TY - JOUR

T1 - The role of NADPH oxidase in chronic intermittent hypoxia-induced pulmonary hypertension in mice

AU - Nisbet, Rachel E.

AU - Graves, Anitra S.

AU - Kleinhenz, Dean J.

AU - Rupnow, Heidi L.

AU - Reed, Alana L.

AU - Fan, Tai-Hwang

AU - Mitchell, Patrick O.

AU - Sutliff, Roy L.

AU - Michael Hart, C.

PY - 2009/5/1

Y1 - 2009/5/1

N2 - Obstructive sleep apnea, characterized by intermittent periods of hypoxemia, is an independent risk factor for the development of pulmonary hypertension. However, the exact mechanisms of this disorder remain to be defined. Enhanced NADP Hoxidase expression and superoxide (O2 -·) generation in the pulmonary vasculature play a critical role in hypoxia-induced pulmonary hypertension. Therefore, the current study explores the hypothesis that chronic intermittent hypoxia (CIH) causes pulmonary hypertension, in part, by increasing NADPH oxidase-derived reactive oxygen species (ROS) that contribute to pulmonary vascular remodeling and hypertension. To test this hypothesis, male C57Bl/6 mice and gp91phox knockout mice were exposed to CIH for 8 hours per day, 5 days per week for 8 weeks. CIH mice were placed in a chamber where the oxygen concentration was cycled between 21% and 10% O2 45 times per hour. Exposure to CIH for 8 weeks increased right ventricular systolic pressure (RVSP), right ventricle (RV):left ventricle (LV) + septum (S) weight ratio, an index of RV hypertrophy, and thickness of the right ventricular anterior wall as measured by echocardiography. CIH exposure also caused pulmonary vascular remodeling as demonstrated by increased muscularization of the distal pulmonary vasculature. CIH-induced pulmonary hypertension was associated with increased lung levels of the NADPH oxidase subunits, Nox4 and p22phox, as well as increased activity of platelet-derived growth factor receptor β and its associated downstream effector, Akt kinase. These CIH-induced derangements were attenuated in similarly treated gp91phox knockout mice. These findings demonstrate that NADPH oxidase-derived ROS contribute to the development of pulmonary vascular remodeling and hypertension caused by CIH.

AB - Obstructive sleep apnea, characterized by intermittent periods of hypoxemia, is an independent risk factor for the development of pulmonary hypertension. However, the exact mechanisms of this disorder remain to be defined. Enhanced NADP Hoxidase expression and superoxide (O2 -·) generation in the pulmonary vasculature play a critical role in hypoxia-induced pulmonary hypertension. Therefore, the current study explores the hypothesis that chronic intermittent hypoxia (CIH) causes pulmonary hypertension, in part, by increasing NADPH oxidase-derived reactive oxygen species (ROS) that contribute to pulmonary vascular remodeling and hypertension. To test this hypothesis, male C57Bl/6 mice and gp91phox knockout mice were exposed to CIH for 8 hours per day, 5 days per week for 8 weeks. CIH mice were placed in a chamber where the oxygen concentration was cycled between 21% and 10% O2 45 times per hour. Exposure to CIH for 8 weeks increased right ventricular systolic pressure (RVSP), right ventricle (RV):left ventricle (LV) + septum (S) weight ratio, an index of RV hypertrophy, and thickness of the right ventricular anterior wall as measured by echocardiography. CIH exposure also caused pulmonary vascular remodeling as demonstrated by increased muscularization of the distal pulmonary vasculature. CIH-induced pulmonary hypertension was associated with increased lung levels of the NADPH oxidase subunits, Nox4 and p22phox, as well as increased activity of platelet-derived growth factor receptor β and its associated downstream effector, Akt kinase. These CIH-induced derangements were attenuated in similarly treated gp91phox knockout mice. These findings demonstrate that NADPH oxidase-derived ROS contribute to the development of pulmonary vascular remodeling and hypertension caused by CIH.

UR - http://www.scopus.com/inward/record.url?scp=65349186285&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=65349186285&partnerID=8YFLogxK

U2 - 10.1165/2008-0145OC

DO - 10.1165/2008-0145OC

M3 - Article

VL - 40

SP - 601

EP - 609

JO - American Journal of Respiratory Cell and Molecular Biology

JF - American Journal of Respiratory Cell and Molecular Biology

SN - 1044-1549

IS - 5

ER -