NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart

Junya Kuroda, Tetsuro Ago, Shoji Matsushima, Peiyong Zhai, Michael D. Schneider, Junichi Sadoshima

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Abstract

NAD(P)H oxidases (Noxs) produce O2- and play an important role in cardiovascular pathophysiology. The Nox4 isoform is expressed primarily in the mitochondria in cardiac myocytes. To elucidate the function of endogenous Nox4 in the heart, we generated cardiac-specific Nox4-/- (c-Nox4-/-) mice. Nox4 expression was inhibited in c-Nox4 -/- mice in a heart-specific manner, and there was no compensatory up-regulationin other Nox enzymes. These mice exhibited reducedlevels of O 2- in the heart, indicating that Nox4 is a significant source of O2- in cardiac myocytes. The baseline cardiac phenotype was normal in young c-Nox4-/- mice. In response to pressure overload (PO), however, increases in Nox4 expression and O2 - production in mitochondria were abolished in c-Nox4-/- mice, and c-Nox4-/- mice exhibited significantly attenuated cardiac hypertrophy, interstitial fibrosis and apoptosis, and better cardiac function compared with WT mice. Mitochondrial swelling, cytochrome c release, and decreases in both mitochondrial DNA and aconitase activity in response to PO were attenuated in c-Nox4-/- mice. On the other hand, overexpression of Nox4 in mouse hearts exacerbated cardiac dysfunction, fibrosis, and apoptosis in response to PO. These results suggest that Nox4 in cardiac myocytes is a major source of mitochondrial oxidative stress, thereby mediating mitochondrial and cardiac dysfunction during PO.

Original languageEnglish
Pages (from-to)15565-15570
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number35
DOIs
Publication statusPublished - Aug 31 2010

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NADPH Oxidase
Oxidative Stress
Cardiac Myocytes
Pressure
Mitochondria
Fibrosis
Aconitate Hydratase
Apoptosis
Mitochondrial Swelling
Cardiomegaly
Cytochromes c
Mitochondrial DNA
Protein Isoforms
Phenotype

All Science Journal Classification (ASJC) codes

  • General

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NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart. / Kuroda, Junya; Ago, Tetsuro; Matsushima, Shoji; Zhai, Peiyong; Schneider, Michael D.; Sadoshima, Junichi.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 35, 31.08.2010, p. 15565-15570.

Research output: Contribution to journalArticle

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