Increased Oxidative Stress in the Nucleus Caused by Nox4 Mediates Oxidation of HDAC4 and Cardiac Hypertrophy
Open accessAbstract
Rationale: Oxidation of cysteine residues in class II histone deacetylases (HDACs), including HDAC4, causes nuclear exit, thereby inducing cardiac hypertrophy. The cellular source of reactive oxygen species responsible for oxidation of HDAC4 remains unknown. Objective: We investigated whether nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4), a major nicotinamide adenine dinucleotide phosphate oxidase, mediates cysteine oxidation of HDAC4. Methods and Results: Phenylephrine (100 μmol/L), an α1 adrenergic agonist, induced upregulation of Nox4 (1.5-fold; P <0.05) within 5 minutes, accompanied by increases in O 2 − (3.5-fold; P <0.01) from the nuclear membrane and nuclear exit of HDAC4 in cardiomyocytes. Knockdown of Nox4, but not Nox2, attenuated O 2 − production in the nucleus and prevented phenylephrine-induced oxidation and nuclear exit of HDAC4. After continuous infusion of phenylephrine (20 mg/kg per day) for 14 days, wild-type and cardiac-specific Nox4 knockout mice exhibited similar aortic pressures. Left ventricular weight/tibial length (5.7±0.2 versus 6.4±0.2 mg/mm; P <0.05) and cardiomyocytes cross-sectional area (223±13 versus 258±12 μm 2 ; P <0.05) were significantly smaller in cardiac-specific Nox4 knockout than in wild-type mice. Nuclear O 2 − production in the heart was significantly lower in cardiac-specific Nox4 knockout than in wild-type mice (4116±314 versus 7057±1710 relative light unit; P <0.05), and cysteine oxidation of HDAC4 was decreased. HDAC4 oxidation and cardiac hypertrophy were also attenuated in cardiac-specific Nox4 knockout mice 2 weeks after transverse aortic constriction. Conclusions: Nox4 plays an essential role in mediating cysteine oxidation and nuclear exit of HDAC4, thereby mediating cardiac hypertrophy in response to phenylephrine and pressure overload.
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ROS influence the activity of epigenetic modulators such as HDACs or DNMTs, with consequences evident in the expression of target genes.
“ROS influence the activity of epigenetic modulators, such as histone deacetylases (HDACs) or DNA methyltransferases (DNMTs) with consequences that are evident in the expression of the target genes38,39.”
From ROS in cancer therapy: the bright side of the moon (2020) · cites this paper as [38]
The Discussion links Nox4-derived ROS to HDAC4 oxidation, and the Results section on NFAT target genes reports changes in transcriptional activity and gene expression. The paper supports the HDAC portion of the claim, but the passages do not address DNA methyltransferases (DNMTs). No page numbers are available in our copy. (LLM, conf=0.88)
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Self-citation
- Authors
- Matsushima, S., Kuroda, J., Ago, T., Zhai, P., Park, J. Y., Xie, L.-H., Tian, B., & Sadoshima, J.
- Affiliations
- University of Medicine and Dentistry of New Jersey (US)
- ORCID
- Venue
- Circulation Research
- Published
- 2013-02-15
- Volume
- 112
- Issue
- 4
- Pages
- 651-663
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC3574183
- OpenAlex
- W2140538799
- Cited by
- 183
- References
- 25
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 11 · 2023: 11 · 2022: 16 · 2021: 9 · 2020: 12 · 2019: 11 · 2018: 11 · 2017: 22 · 2016: 20 · 2015: 16 · 2014: 14 · 2013: 10
- FWCI
- 8.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Japan Society for the Promotion of Science (21390243)
- National Institute on Aging (AG23039, R01AG023039, R21AG042678)
- National Heart, Lung, and Blood Institute (R21HL098802, HL91469, R01HL067724, HL102738, R01HL102738, R01HL112330, HL-67724, R01HL091469, HL112330)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Keywords
- NOX4, HDAC4, cysteine oxidation, cardiac hypertrophy, superoxide, class II histone deacetylases, phenylephrine, pressure overload, transverse aortic constriction, cardiomyocytes, oxidative stress
- MeSH terms
- NADPH Oxidase 2, NADPH Oxidase 4, Animals, Aortic Valve Stenosis, Cell Nucleus, Cysteine, Enzyme Activation, Enzyme Induction, Cardiomegaly, Histone Deacetylases, Male, Membrane Glycoproteins, Mice, Transgenic, Nuclear Envelope, Oxidation-Reduction, Phenylephrine, Recombinant Fusion Proteins, Reactive Oxygen Species, Mice, Knockout, Oxidative Stress, NADPH Oxidases, Protein Transport, Myocytes, Cardiac, Cell Size, Mice, Rats
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