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Inhibition of NADPH oxidase 2 (NOX2) prevents sepsis-induced cardiomyopathy by improving calcium handling and mitochondrial function
Leroy C. Joseph, … , Konstantinos Drosatos, John P. Morrow
Leroy C. Joseph, … , Konstantinos Drosatos, John P. Morrow
Published September 7, 2017
Citation Information: JCI Insight. 2017;2(17):e94248. https://doi.org/10.1172/jci.insight.94248.
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Research Article Cardiology

Inhibition of NADPH oxidase 2 (NOX2) prevents sepsis-induced cardiomyopathy by improving calcium handling and mitochondrial function

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Abstract

Cardiomyopathy frequently complicates sepsis and is associated with increased mortality. Increased cardiac oxidative stress and mitochondrial dysfunction have been observed during sepsis, but the mechanisms responsible for these abnormalities have not been determined. We hypothesized that NADPH oxidase 2 (NOX2) activation could be responsible for sepsis-induced oxidative stress and cardiomyopathy. Treatment of isolated adult mouse cardiomyocytes with low concentrations of the endotoxin lipopolysaccharide (LPS) increased total cellular reactive oxygen species (ROS) and mitochondrial superoxide. Elevated mitochondrial superoxide was accompanied by depolarization of the mitochondrial inner membrane potential, an indication of mitochondrial dysfunction, and mitochondrial calcium overload. NOX2 inhibition decreased LPS-induced superoxide and prevented mitochondrial dysfunction. Further, cardiomyocytes from mice with genetic ablation of NOX2 did not have LPS-induced superoxide or mitochondrial dysfunction. LPS decreased contractility and calcium transient amplitude in isolated cardiomyocytes, and these abnormalities were prevented by inhibition of NOX2. LPS decreased systolic function in mice, measured by echocardiography. NOX2 inhibition was cardioprotective in 2 mouse models of sepsis, preserving systolic function after LPS injection or cecal ligation and puncture (CLP). These data show that inhibition of NOX2 decreases oxidative stress, preserves intracellular calcium handling and mitochondrial function, and alleviates sepsis-induced systolic dysfunction in vivo. Thus, NOX2 is a potential target for pharmacotherapy of sepsis-induced cardiomyopathy.

Authors

Leroy C. Joseph, Dimitra Kokkinaki, Mesele-Christina Valenti, Grace J. Kim, Emanuele Barca, Dhanendra Tomar, Nicholas E. Hoffman, Prakash Subramanyam, Henry M. Colecraft, Michio Hirano, Adam J. Ratner, Muniswamy Madesh, Konstantinos Drosatos, John P. Morrow

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Figure 1

LPS increases oxidative stress in cardiomyocytes and causes mitochondrial dysfunction.

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LPS increases oxidative stress in cardiomyocytes and causes mitochondria...
(A) Representative experiment done with WT adult mouse ventricular myocytes (AMVMs) in triplicate wells, 2,000 cells/well; height is DCF fluorescence minus background, arbitrary units, in live cells, mean + SEM. LPS increases ROS significantly. LPS = lipopolysaccharide 5 or 20 ng/ml as noted, 1-hour exposure. (B) Cardiomyocytes from the same experiment using MitoSOX Red readout, arbitrary units, to indicate mitochondrial superoxide. (C) Cardiomyocytes from the same experiment using TMRM readout to indicate mitochondrial inner membrane depolarization. (D) Cardiomyocytes from the same experiment using Rhod 2-AM readout, arbitrary units, to indicate mitochondrial calcium load. For panels A–D, means are significantly different by ANOVA; *significantly different from control by post-hoc test. (E) Maximum oxygen consumption rate (OCR) is decreased in H9c2 cells by LPS. Measurements from 3 time points were obtained under each condition, using triplicate wells. P = 0.014 for comparison of control with 2-hour LPS at the FCCP step (to stimulate maximum oxygen consumption). b, baseline; o, oligomycin; F, FCCP; AA, antimycin-A and rotenone.

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