Cited by 99Mitochondrial Function and PathologyCardiac Ischemia and ReperfusionNitric Oxide and Endothelin Effects

Inhibition of NAPDH Oxidase 2 (NOX2) Prevents Oxidative Stress and Mitochondrial Abnormalities Caused by Saturated Fat in Cardiomyocytes

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Joseph, Leroy C., Barca, Emanuele, Subramanyam, Prakash, Komrowski, Michael, Pajvani, Utpal, Colecraft, Henry M., Hirano, Michio, Morrow, John P.·2016·PLOS ONE

Abstract

Obesity and high saturated fat intake increase the risk of heart failure and arrhythmias. The molecular mechanisms are poorly understood. We hypothesized that physiologic levels of saturated fat could increase mitochondrial reactive oxygen species (ROS) in cardiomyocytes, leading to abnormalities of calcium homeostasis and mitochondrial function. We investigated the effect of saturated fat on mitochondrial function and calcium homeostasis in isolated ventricular myocytes. The saturated fatty acid palmitate causes a decrease in mitochondrial respiration in cardiomyocytes. Palmitate, but not the monounsaturated fatty acid oleate, causes an increase in both total cellular ROS and mitochondrial ROS. Palmitate depolarizes the mitochondrial inner membrane and causes mitochondrial calcium overload by increasing sarcoplasmic reticulum calcium leak. Inhibitors of PKC or NOX2 prevent mitochondrial dysfunction and the increase in ROS, demonstrating that PKC-NOX2 activation is also required for amplification of palmitate induced-ROS. Cardiomyocytes from mice with genetic deletion of NOX2 do not have palmitate-induced ROS or mitochondrial dysfunction. We conclude that palmitate induces mitochondrial ROS that is amplified by NOX2, causing greater mitochondrial ROS generation and partial depolarization of the mitochondrial inner membrane. The abnormal sarcoplasmic reticulum calcium leak caused by palmitate could promote arrhythmia and heart failure. NOX2 inhibition is a potential therapy for heart disease caused by diabetes or obesity.

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  • STAT3 can directly regulate mitochondrial function, and Nox2 can modulate mitochondrial activity.

    “STAT3 can directly regulate mitochondrial function [97,98], and Nox2 can modulate mitochondrial activity [99][100][101]”

    From Parvalbumin interneuron vulnerability and brain disorders (2021) · cites this paper as [100]

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  1. [56]Rodrigo R, Korantzopoulos P, Cereceda M, Asenjo R, Zamorano J, Villalabeitia E, et al A randomized controlled trial to prevent post-operative atrial fibrillation by antioxidant reinforcement. J Am Coll Cardiol. 2013; 62: 1457– 65. 10.1016/j.jacc.2013.07.014 23916928 · DOI · Paper page

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Authors
Joseph, L. C., Barca, E., Subramanyam, P., Komrowski, M., Pajvani, U., Colecraft, H. M., Hirano, M., & Morrow, J. P.
Affiliations
Columbia University (US)
Corresponding author
Morrow, John P.
Venue
PLOS ONE
Published
2016-01-12
Volume
11
Issue
1
Pages
e0145750
ISSN
1932-6203 (ISSN-L)
OpenAlex
W2239356987
Cited by
99
References
57
Citations by year
2026: 5 · 2025: 5 · 2024: 8 · 2023: 8 · 2022: 13 · 2021: 13 · 2020: 16 · 2019: 13 · 2018: 5 · 2017: 11 · 2016: 2
FWCI
5.37
Type
journal article
Language
en
Open access
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • Columbia Academic Commons (Columbia University)
Funders
  • National Institutes of Health (CA013696)
  • National Heart, Lung, and Blood Institute (K08HL105801)
  • National Cancer Institute (CA013696, P30CA013696)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD080642)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Keywords
NOX2 inhibition, saturated fat, palmitate, oleate, cardiomyocytes, mitochondrial reactive oxygen species, mitochondrial dysfunction, mitochondrial calcium overload, sarcoplasmic reticulum calcium leak, mitochondrial depolarization, protein kinase C, oxidative stress, heart failure, cardiac arrhythmias, obesity, diabetes mellitus
MeSH terms
NADPH Oxidase 2, Animals, Antimycin A, Antioxidants, Calcium, Cell Line, Electron Transport, Heart Ventricles, Homeostasis, Male, Membrane Glycoproteins, Mice, Inbred C57BL, Mitochondria, Oxygen Consumption, Palmitates, Protein Kinase C, Sarcoplasmic Reticulum, Signal Transduction, Apoptosis, Gene Deletion, Reactive Oxygen Species, Mice, Knockout, Oxidative Stress, NADPH Oxidases, Muscle Cells, Myocytes, Cardiac, Mice

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