Broad suppression of NADPH oxidase activity exacerbates ischemia/reperfusion injury through inadvertent downregulation of hypoxia-inducible factor-1α and upregulation of peroxisome proliferator-activated receptor-α

Shoji Matsushima, Junya Kuroda, Tetsuro Ago, Peiyong Zhai, Yoshiyuki Ikeda, Shinichi Oka, Guo Hua Fong, Rong Tian, Junichi Sadoshima

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

RATIONALE: NADPH oxidase (Nox) 2 and Nox4 are major components of the Nox family which purposefully produce reactive oxidative species, namely O 2- and H2O2, in the heart. The isoform-specific contribution of Nox2 and Nox4 to ischemia/reperfusion (I/R) injury is poorly understood. OBJECTIVE: We investigated the role of Nox2 and Nox4 in mediating oxidative stress and myocardial injury during I/R using loss-of-function mouse models. METHODS AND RESULTS: Systemic (s) Nox2 knockout (KO), sNox4 KO, and cardiac-specific (c) Nox4 KO mice were subjected to I/R (30 minutes/24 hours, respectively). Both myocardial infarct size/area at risk and O2- production were lower in sNox2 KO, sNox4 KO, and cNox4 KO than in wild-type mice. Unexpectedly, however, the myocardial infarct size/area at risk was greater, despite less O2- production, in sNox2 KO+cNox4 KO (double-KO) mice and transgenic mice (Tg) with cardiac-specific expression of dominant-negative Nox, which suppresses both Nox2 and Nox4, than in wild-type or single KO mice. Hypoxia-inducible factor-1α was downregulated whereas peroxisome proliferator-activated receptor-α was upregulated in Tg-dominant-negative Nox mice. A cross with mice deficient in prolyl hydroxylase 2, which hydroxylates hypoxia-inducible factor-1α, rescued the I/R injury and prevented upregulation of peroxisome proliferator-activated receptor-α in Tg-dominant-negative Nox mice. A cross with peroxisome proliferator-activated receptor-α KO mice also attenuated the injury in Tg- dominant-negative Nox mice. CONCLUSIONS: Both Nox2 and Nox4 contribute to the increase in reactive oxidative species and injury by I/R. However, low levels of reactive oxidative species produced by either Nox2 or Nox4 regulate hypoxia-inducible factor-1α and peroxisome proliferator-activated receptor-α, thereby protecting the heart against I/R, suggesting that Noxs also act as a physiological sensor for myocardial adaptation.

Original languageEnglish
Pages (from-to)1135-1149
Number of pages15
JournalCirculation research
Volume112
Issue number8
DOIs
Publication statusPublished - Apr 12 2013

Fingerprint

Hypoxia-Inducible Factor 1
Peroxisome Proliferator-Activated Receptors
NADPH Oxidase
Reperfusion Injury
Up-Regulation
Down-Regulation
Knockout Mice
Reperfusion
Ischemia
Myocardial Infarction
Prolyl Hydroxylases
Wounds and Injuries
Transgenic Mice
Protein Isoforms
Oxidative Stress

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Broad suppression of NADPH oxidase activity exacerbates ischemia/reperfusion injury through inadvertent downregulation of hypoxia-inducible factor-1α and upregulation of peroxisome proliferator-activated receptor-α. / Matsushima, Shoji; Kuroda, Junya; Ago, Tetsuro; Zhai, Peiyong; Ikeda, Yoshiyuki; Oka, Shinichi; Fong, Guo Hua; Tian, Rong; Sadoshima, Junichi.

In: Circulation research, Vol. 112, No. 8, 12.04.2013, p. 1135-1149.

Research output: Contribution to journalArticle

@article{8b280e3d49c94506871cecf2d5c6cfbc,
title = "Broad suppression of NADPH oxidase activity exacerbates ischemia/reperfusion injury through inadvertent downregulation of hypoxia-inducible factor-1α and upregulation of peroxisome proliferator-activated receptor-α",
abstract = "RATIONALE: NADPH oxidase (Nox) 2 and Nox4 are major components of the Nox family which purposefully produce reactive oxidative species, namely O 2- and H2O2, in the heart. The isoform-specific contribution of Nox2 and Nox4 to ischemia/reperfusion (I/R) injury is poorly understood. OBJECTIVE: We investigated the role of Nox2 and Nox4 in mediating oxidative stress and myocardial injury during I/R using loss-of-function mouse models. METHODS AND RESULTS: Systemic (s) Nox2 knockout (KO), sNox4 KO, and cardiac-specific (c) Nox4 KO mice were subjected to I/R (30 minutes/24 hours, respectively). Both myocardial infarct size/area at risk and O2- production were lower in sNox2 KO, sNox4 KO, and cNox4 KO than in wild-type mice. Unexpectedly, however, the myocardial infarct size/area at risk was greater, despite less O2- production, in sNox2 KO+cNox4 KO (double-KO) mice and transgenic mice (Tg) with cardiac-specific expression of dominant-negative Nox, which suppresses both Nox2 and Nox4, than in wild-type or single KO mice. Hypoxia-inducible factor-1α was downregulated whereas peroxisome proliferator-activated receptor-α was upregulated in Tg-dominant-negative Nox mice. A cross with mice deficient in prolyl hydroxylase 2, which hydroxylates hypoxia-inducible factor-1α, rescued the I/R injury and prevented upregulation of peroxisome proliferator-activated receptor-α in Tg-dominant-negative Nox mice. A cross with peroxisome proliferator-activated receptor-α KO mice also attenuated the injury in Tg- dominant-negative Nox mice. CONCLUSIONS: Both Nox2 and Nox4 contribute to the increase in reactive oxidative species and injury by I/R. However, low levels of reactive oxidative species produced by either Nox2 or Nox4 regulate hypoxia-inducible factor-1α and peroxisome proliferator-activated receptor-α, thereby protecting the heart against I/R, suggesting that Noxs also act as a physiological sensor for myocardial adaptation.",
author = "Shoji Matsushima and Junya Kuroda and Tetsuro Ago and Peiyong Zhai and Yoshiyuki Ikeda and Shinichi Oka and Fong, {Guo Hua} and Rong Tian and Junichi Sadoshima",
year = "2013",
month = "4",
day = "12",
doi = "10.1161/CIRCRESAHA.111.300171",
language = "English",
volume = "112",
pages = "1135--1149",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "8",

}

TY - JOUR

T1 - Broad suppression of NADPH oxidase activity exacerbates ischemia/reperfusion injury through inadvertent downregulation of hypoxia-inducible factor-1α and upregulation of peroxisome proliferator-activated receptor-α

AU - Matsushima, Shoji

AU - Kuroda, Junya

AU - Ago, Tetsuro

AU - Zhai, Peiyong

AU - Ikeda, Yoshiyuki

AU - Oka, Shinichi

AU - Fong, Guo Hua

AU - Tian, Rong

AU - Sadoshima, Junichi

PY - 2013/4/12

Y1 - 2013/4/12

N2 - RATIONALE: NADPH oxidase (Nox) 2 and Nox4 are major components of the Nox family which purposefully produce reactive oxidative species, namely O 2- and H2O2, in the heart. The isoform-specific contribution of Nox2 and Nox4 to ischemia/reperfusion (I/R) injury is poorly understood. OBJECTIVE: We investigated the role of Nox2 and Nox4 in mediating oxidative stress and myocardial injury during I/R using loss-of-function mouse models. METHODS AND RESULTS: Systemic (s) Nox2 knockout (KO), sNox4 KO, and cardiac-specific (c) Nox4 KO mice were subjected to I/R (30 minutes/24 hours, respectively). Both myocardial infarct size/area at risk and O2- production were lower in sNox2 KO, sNox4 KO, and cNox4 KO than in wild-type mice. Unexpectedly, however, the myocardial infarct size/area at risk was greater, despite less O2- production, in sNox2 KO+cNox4 KO (double-KO) mice and transgenic mice (Tg) with cardiac-specific expression of dominant-negative Nox, which suppresses both Nox2 and Nox4, than in wild-type or single KO mice. Hypoxia-inducible factor-1α was downregulated whereas peroxisome proliferator-activated receptor-α was upregulated in Tg-dominant-negative Nox mice. A cross with mice deficient in prolyl hydroxylase 2, which hydroxylates hypoxia-inducible factor-1α, rescued the I/R injury and prevented upregulation of peroxisome proliferator-activated receptor-α in Tg-dominant-negative Nox mice. A cross with peroxisome proliferator-activated receptor-α KO mice also attenuated the injury in Tg- dominant-negative Nox mice. CONCLUSIONS: Both Nox2 and Nox4 contribute to the increase in reactive oxidative species and injury by I/R. However, low levels of reactive oxidative species produced by either Nox2 or Nox4 regulate hypoxia-inducible factor-1α and peroxisome proliferator-activated receptor-α, thereby protecting the heart against I/R, suggesting that Noxs also act as a physiological sensor for myocardial adaptation.

AB - RATIONALE: NADPH oxidase (Nox) 2 and Nox4 are major components of the Nox family which purposefully produce reactive oxidative species, namely O 2- and H2O2, in the heart. The isoform-specific contribution of Nox2 and Nox4 to ischemia/reperfusion (I/R) injury is poorly understood. OBJECTIVE: We investigated the role of Nox2 and Nox4 in mediating oxidative stress and myocardial injury during I/R using loss-of-function mouse models. METHODS AND RESULTS: Systemic (s) Nox2 knockout (KO), sNox4 KO, and cardiac-specific (c) Nox4 KO mice were subjected to I/R (30 minutes/24 hours, respectively). Both myocardial infarct size/area at risk and O2- production were lower in sNox2 KO, sNox4 KO, and cNox4 KO than in wild-type mice. Unexpectedly, however, the myocardial infarct size/area at risk was greater, despite less O2- production, in sNox2 KO+cNox4 KO (double-KO) mice and transgenic mice (Tg) with cardiac-specific expression of dominant-negative Nox, which suppresses both Nox2 and Nox4, than in wild-type or single KO mice. Hypoxia-inducible factor-1α was downregulated whereas peroxisome proliferator-activated receptor-α was upregulated in Tg-dominant-negative Nox mice. A cross with mice deficient in prolyl hydroxylase 2, which hydroxylates hypoxia-inducible factor-1α, rescued the I/R injury and prevented upregulation of peroxisome proliferator-activated receptor-α in Tg-dominant-negative Nox mice. A cross with peroxisome proliferator-activated receptor-α KO mice also attenuated the injury in Tg- dominant-negative Nox mice. CONCLUSIONS: Both Nox2 and Nox4 contribute to the increase in reactive oxidative species and injury by I/R. However, low levels of reactive oxidative species produced by either Nox2 or Nox4 regulate hypoxia-inducible factor-1α and peroxisome proliferator-activated receptor-α, thereby protecting the heart against I/R, suggesting that Noxs also act as a physiological sensor for myocardial adaptation.

UR - http://www.scopus.com/inward/record.url?scp=84876371833&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84876371833&partnerID=8YFLogxK

U2 - 10.1161/CIRCRESAHA.111.300171

DO - 10.1161/CIRCRESAHA.111.300171

M3 - Article

C2 - 23476056

AN - SCOPUS:84876371833

VL - 112

SP - 1135

EP - 1149

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 8

ER -