Abstract
Patients with heart failure (HF) have diaphragm abnormalities that contribute to disease morbidity and mortality. Studies in animals suggest that reactive oxygen species (ROS) cause diaphragm abnormalities in HF. However, the effects of HF on ROS sources, antioxidant enzymes, and protein oxidation in the diaphragm of humans is unknown. NAD(P)H oxidase, especially the Nox2 isoform, is an important source of ROS in the diaphragm. Our main hypothesis was that diaphragm from patients with HF have heightened Nox2 expression and p47phox phosphorylation (marker of enzyme activation) that is associated with elevated protein oxidation. We collected diaphragm biopsies from patients with HF and brain-dead organ donors (controls). Diaphragm mRNA levels of Nox2 subunits were increased 2.5–4.6-fold over controls (p < 0.05). Patients also had increased protein levels of Nox2 subunits (p47phox, p22phox, and p67phox) and total p47phox phosphorylation, while phospho-to-total p47phox levels were unchanged. The antioxidant enzyme catalase was increased in patients, whereas glutathione peroxidase and superoxide dismutases were unchanged. Among markers of protein oxidation, carbonyls were increased by ~40% (p < 0.05) and 4-hydroxynonenal and 3-nitrotyrosines were unchanged in patients with HF. Overall, our findings suggest that Nox2 is an important source of ROS in the diaphragm of patients with HF and increases in levels of antioxidant enzymes are not sufficient to maintain normal redox homeostasis. The net outcome is elevated diaphragm protein oxidation that has been shown to cause weakness in animals.
Document Type
Article
Publication Date
1-9-2017
Digital Object Identifier (DOI)
https://doi.org/10.3389/fphys.2016.00686
Funding Information
This study was funded by NIH grant R00-HL098453 to LF. AJ was funded by NIH grant R01 AR060209.
Repository Citation
Ahn, Bumsoo; Coblentz, Philip D.; Beharry, Adam W.; Patel, Nikhil; Judge, Andrew R.; Moylan, Jennifer S.; Hoopes, Charles W.; Bonnell, Mark R.; and Ferreira, Leonardo F., "Diaphragm Abnormalities in Patients with End-Stage Heart Failure: NADPH Oxidase Upregulation and Protein Oxidation" (2017). Physiology Faculty Publications. 97.
https://uknowledge.uky.edu/physiology_facpub/97
Notes/Citation Information
Published in Frontiers in Physiology, v. 7, article 686, p. 1-9.
Copyright © 2017 Ahn, Coblentz, Beharry, Patel, Judge, Moylan, Hoopes, Bonnell and Ferreira.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.