Abstract
NADPH Oxidase 4-mediated Fibrosis Contributes to Heart Failure with Preserved Ejection Fraction
Free radical biology & medicine, Vol.192, pp.70-70
11/01/2022
DOI: 10.1016/j.freeradbiomed.2022.10.119
Abstract
Whereas patients with heart failure with reduced ejection fraction (HFrEF) have therapies to improve quality of life and survival, there are no treatments for heart failure with preserved left ventricular ejection fraction (HFpEF). Cardiac fibrosis and left ventricular non-compliance are responsible for HFpEF. TGFß is a central mediator of fibrogenesis and an upstream mediator of Nox4 NADPH oxidase activation. The goal of this study was to evaluate the role of Nox4 in the development of HFpEF. Using an established combinatorial metabolic (high-fat diet) and mechanical (NOS inhibition) mouse model of HFpEF for ten weeks, wildtype mice demonstrated reduced maximal exercise capacity and elevated natriuretic peptide levels, which were prevented by deficiency of Nox4. Histologic and biochemical markers of cardiac hypertrophy, fibrosis, and inflammation were increased in HFpEF mice compared to control mice and attenuated in HFpEF Nox4 knockout animals. Importantly, wildtype and Nox4 deficient mice in the HFpEF groups demonstrated similar weight gain, glucose tolerance, and insulin tolerance. Metabolomic analysis of the heart included assessing acylcarnitines, amino acids, organic acids, and nucleotides, revealing the accumulation of long chain acylcarnitines in the wildtype HFpEF animals compared to control, but not the Nox4 knockout HFpEF animals. RNA sequencing of the heart showed changes in the expression of genes associated with metabolism and ATP production. The inability to generate energy is a central mechanism linking mitochondrial dysfunction and heart failure. Cell lysates containing nanoluciferase Nox4 were passed over gamma-phosphate-linked ATP Sepharose beads and confirmed the binding of Nox4 to ATP at nanomolar concentrations. Wildtype HFpEF animals showed diminished ATP levels, whereas Nox4 knockout animals had increased ATP levels. These data suggest that Nox4 is central to the pathogenesis of HFpEF pleiotropically regulating inflammation, fibrosis, and metabolism. Inhibition of Nox4 may provide a therapeutic avenue to treat HFpEF.
Details
- Title: Subtitle
- NADPH Oxidase 4-mediated Fibrosis Contributes to Heart Failure with Preserved Ejection Fraction
- Creators
- Brandon Schickling - University of IowaFranziska Bollmann - Duke UniversityAnna Schwarzkopf - Duke UniversityKamie Snow - Duke UniversityFrancis Miller - Duke University
- Resource Type
- Abstract
- Publication Details
- Free radical biology & medicine, Vol.192, pp.70-70
- DOI
- 10.1016/j.freeradbiomed.2022.10.119
- ISSN
- 0891-5849
- eISSN
- 1873-4596
- Publisher
- Elsevier Inc
- Number of pages
- 1
- Language
- English
- Date published
- 11/01/2022
- Academic Unit
- Obstetrics and Gynecology
- Record Identifier
- 9984966838402771
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