NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart
Open accessAbstract
NAD(P)H oxidases (Noxs) produce O 2 − 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-regulation in other Nox enzymes. These mice exhibited reduced levels of O 2 − in the heart, indicating that Nox4 is a significant source of O 2 − 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 O 2 − 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.
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In the heart, NOX4 promotes adaptive cardiac remodeling in a disease setting of chronic pressure overload.
“Previous studies have shown that in the heart, NOX4 promotes adaptive cardiac remodeling in a disease setting of chronic pressure overload (34, 38)”
From Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance (2021) · cites this paper as [34]
Studies with rat AO have shown a significant production of superoxide when the enzyme uses NADH as a substrate.
“Studies with rat AO have shown a significant production of superoxide when the enzyme uses NADH as a substrate (539).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [539]
The Mo-containing protein AO has been described as a potential source of superoxide in vivo.
“The Mo-containing protein AO has also been described as a potential source of superoxide in vivo (538, 539).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [539]
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- Authors
- Kuroda, J., Ago, T., Matsushima, S., Zhai, P., Schneider, M. D., & Sadoshima, J.
- Affiliations
- Rutgers New Jersey Medical School (US)
- Imperial College London (GB)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-08-16
- Volume
- 107
- Issue
- 35
- Pages
- 15565-15570
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2932625
- OpenAlex
- W1977551186
- Cited by
- 772
- References
- 30
- Citations by year
- 2026: 24 · 2025: 31 · 2024: 38 · 2023: 61 · 2022: 47 · 2021: 43 · 2020: 41 · 2019: 49 · 2018: 49 · 2017: 51 · 2016: 52 · 2015: 53 · 2014: 51 · 2013: 66 · 2012: 81
- FWCI
- 39.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P01AG027211, R01AG023039, AG27211)
- National Heart, Lung, and Blood Institute (HL59139, HL91469, R01HL067724, HL69020, R01HL102738, HL-67724, P01HL059139, P01HL069020, R01HL091469)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- NOX4, mitochondrial superoxide, oxidative stress, heart failure, pressure overload, cardiac hypertrophy, myocardial fibrosis, apoptosis, mitochondrial dysfunction, cytochrome c release, mitochondrial DNA damage, aconitase, cardiomyocytes, cardiac-specific knockout mice
- MeSH terms
- NADPH Oxidase 4, Animals, Echocardiography, Female, Heart, Cardiomegaly, Heart Failure, Isoenzymes, Male, Mice, Inbred C57BL, Mitochondria, Myocardium, Immunoblotting, Apoptosis, Reactive Oxygen Species, Mice, Knockout, Oxidative Stress, NADPH Oxidases, Reverse Transcriptase Polymerase Chain Reaction, In Situ Nick-End Labeling, Myocytes, Cardiac, Mice
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