Upregulation of Nox4 by Hypertrophic Stimuli Promotes Apoptosis and Mitochondrial Dysfunction in Cardiac Myocytes
Open accessAbstract
Rationale : NADPH oxidases are a major source of superoxide (O 2 − ) in the cardiovascular system. The function of Nox4, a member of the Nox family of NADPH oxidases, in the heart is poorly understood. Objective : The goal of this study was to elucidate the role of Nox4 in mediating oxidative stress and growth/death in the heart. Methods and Results : Expression of Nox4 in the heart was increased in response to hypertrophic stimuli and aging. Neither transgenic mice with cardiac specific overexpression of Nox4 (Tg-Nox4) nor those with catalytically inactive Nox4 (Tg-Nox4-P437H) showed an obvious baseline cardiac phenotype at young ages. Tg-Nox4 gradually displayed decreased left ventricular (LV) function with enhanced O 2 − production in the heart, which was accompanied by increased apoptosis and fibrosis at 13 to 14 months of age. On the other hand, the level of oxidative stress was attenuated in Tg-Nox4-P437H. Although the size of cardiac myocytes was significantly greater in Tg-Nox4 than in nontransgenic, the LV weight/tibial length was not significantly altered in Tg-Nox4 mice. Overexpression of Nox4 in cultured cardiac myocytes induced apoptotic cell death but not hypertrophy. Nox4 is primarily localized in mitochondria and upregulation of Nox4 enhanced both rotenone- and diphenyleneiodonium-sensitive O 2 − production in mitochondria. Cysteine residues in mitochondrial proteins, including aconitase and NADH dehydrogenases, were oxidized and their activities decreased in Tg-Nox4. Conclusions : Upregulation of Nox4 by hypertrophic stimuli and aging induces oxidative stress, apoptosis and LV dysfunction, in part because of mitochondrial insufficiency caused by increased O 2 − production and consequent cysteine oxidation in mitochondrial proteins.
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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 [38]
Activated NOX can increase ROS production by the mitochondria.
“Indeed, activated NOX can in turn, increase ROS production by the mitochondria (11, 116).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [11]
The N-terminal region of NOX4 is capable of targeting proteins to mitochondria.
“This report of a cardiac mitochondrial NOX4 also provided experimental evidence that the N-terminal region of NOX4 is capable of targeting proteins to the mitochondria.”
From Redox regulation of mitochondrial function (2012) · cites this paper as [4]
In mouse heart, endogenous NOX4 is found in both mitochondria and microsomal fractions.
“In mouse heart, however, endogenous NOX4 has been found in both mitochondria and microsomal fractions (4).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [4]
The increase in cardiac mitochondrial ROS following hypertrophic stimuli is due to both increases in NOX4 expression and enhanced mitochondrial-dependent ROS production.
“Notably, the increase in cardiac mitochondrial ROS following these hypertrophic stimuli was found to be due to both increases in NOX4 expression as well as enhanced mitochondrial-dependent ROS production”
From Redox regulation of mitochondrial function (2012) · cites this paper as [4]
In mouse hearts, chronic treatments with pressor agents (AII, phenylephrine) and transverse aortic constriction increase NOX4 expression.
“In mouse hearts, chronic treatments with pressor agents (AII, phenylephrine) and transverse aortic constriction (TAC) were found to increase NOX4 expression.”
From Redox regulation of mitochondrial function (2012) · cites this paper as [4]
Cardiac expression of NOX4 increases during normal aging.
“In addition, cardiac expression of NOX4 was found to increase during normal aging (4).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [4]
Forced upregulation of mitochondrial NOX4 in the heart increases thiol oxidation of many mitochondrial proteins including ETC complex I, aconitase, and other TCA enzymes.
“forced upregulation of mitochondrial NOX4 in the heart, by using a targeted transgene, increased thiol oxidation of many mitochondrial proteins including the ETC complex I, aconitase, and other TCA enzymes (4).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [4]
Cardiac overexpression of NOX4 causes a decrease in mitochondrial biogenic signal, resulting in decreased levels of mtDNA in cardiomyocytes.
“cardiac overexpression of NOX4 also caused a decrease in the mitochondrial biogenic signal in the heart, resulting in decreased levels of mitochondrial DNA (mtDNA) in cardiomyocytes from these overexpressing mice.”
From Redox regulation of mitochondrial function (2012) · cites this paper as [4]
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Self-citation
- Authors
- Ago, T., Kuroda, J., Pain, J., Fu, C., Li, H., & Sadoshima, J.
- Affiliations
- Cardiovascular Institute Hospital (JP)
- From the Department of Cell Biology and Molecular Medicine (T.A., J.K., J.P., J.S.), Cardiovascular Research Institute; and Center for Advanced Proteomics Research (C.F., H.L.), Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark.
- Corresponding author
- Sadoshima, Junichi
- Venue
- Circulation Research
- Published
- 2010-04-16
- Volume
- 106
- Issue
- 7
- Pages
- 1253-1264
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC2855780
- OpenAlex
- W2148030708
- Cited by
- 506
- References
- 33
- Citations by year
- 2026: 13 · 2025: 20 · 2024: 17 · 2023: 26 · 2022: 35 · 2021: 27 · 2020: 33 · 2019: 14 · 2018: 38 · 2017: 37 · 2016: 33 · 2015: 32 · 2014: 33 · 2013: 44 · 2012: 57
- FWCI
- 32.05
- 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 (P01AG027211, R01AG023039, AG27211, R01AG028787)
- National Heart, Lung, and Blood Institute (R41HL079729, HL59139, R01HL067727, HL91469, R01HL067724, HL69020, R01HL102738, HL-67724, P01HL059139, R01HL033107, 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, NADPH oxidase, cardiac hypertrophy, apoptosis, mitochondrial dysfunction, oxidative stress, superoxide, cardiac aging, left ventricular dysfunction, myocardial fibrosis, aconitase, NADH dehydrogenase, cardiomyocytes, transgenic mice
- MeSH terms
- NADPH Oxidase 4, Aconitate Hydratase, Aging, Animals, Cells, Cultured, Cysteine, Disease Models, Animal, Enzyme Inhibitors, Fibrosis, Genotype, Cardiomegaly, Humans, Mice, Transgenic, Mitochondria, Heart, NADH Dehydrogenase, Onium Compounds, Oxidation-Reduction, Phenotype, Rotenone, Superoxides, Transfection, Uncoupling Agents, Up-Regulation, Ventricular Function, Left, Rats, Wistar, Apoptosis, Oxidative Stress, Ventricular Dysfunction, Left, NADPH Oxidases, Myocytes, Cardiac, Cell Proliferation, Mice, Rats
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