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.

Highlights

  • Patients with end-stage heart failure (HF) have respiratory complications that contribute to disease morbidity and mortality

  • Diaphragm mRNA levels of Nox2, p22phox, p47phox, p67phox, and p40phox were increased with median values ranging from 2.5- to 4.6-fold over controls (Figure 1)

  • The protein levels of Nox2, p47phox, p22phox, and p67phox were increased in diaphragm of HF patients, while protein levels of Rac1 was not significantly changed (Figure 1)

Read more

Summary

Introduction

Patients with end-stage heart failure (HF) have respiratory complications that contribute to disease morbidity and mortality. The incidence of pneumonia in end-stage HF patients who receive a heart transplant is 15–20% and 5% of patients have prolonged respiratory failure post-heart transplant (Lenner et al, 2001). The cause of pneumonia and respiratory failure in end-stage HF patients is multifactorial. In this context, inspiratory muscle abnormalities in patients with end-stage HF can play a critical role in respiratory complications (Kelley and Ferreira, 2016). Nox and Protein Oxidation in Heart Failure pre-operative inspiratory muscle strength training reduces the incidence of post-operative pulmonary complications in “highrisk” patients, including those with HF, undergoing coronary artery bypass graft (Hulzebos et al, 2006). Less is known about the underlying mechanisms of diaphragm dysfunction in end-stage HF

Methods
Results
Discussion
Conclusion
Full Text
Paper version not known

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.