Back to Search
Start Over
Elimination of NADPH oxidase activity promotes reductive stress and sensitizes the heart to ischemic injury.
- Source :
-
Journal of the American Heart Association [J Am Heart Assoc] 2014 Jan 27; Vol. 3 (1), pp. e000555. Date of Electronic Publication: 2014 Jan 27. - Publication Year :
- 2014
-
Abstract
- Background: The NADPH oxidase family (Nox) produces reactive oxygen species by adding the electron donated by NADPH to oxygen. Excessive reactive oxygen species production under a variety of pathological conditions has been attributed to increased Nox activity. Here, we aimed at investigating the role of Nox in cardiac ischemic injury through gain- and loss-of-function approaches.<br />Methods and Results: We modulated Nox activity in the heart by cardiac-specific expression of Nox4 and dominant negative Nox4. Modulation of Nox activity drastically changes the cellular redox status. Increasing Nox activity by cardiac-specific overexpression of Nox4 imposed oxidative stress on the myocardium [increased NAD(P)(+)/NAD(P)H and decreased glutathione/glutathione disulfide ratio] and worsened cardiac energetics and contractile function after ischemia-reperfusion. Overexpression of the dominant negative Nox4 (DN), which abolished the Nox function, led to a markedly reduced state [decreased NAD(P)(+)/NAD(P)H and increased glutathione/glutathione disulfide ratio] at baseline and paradoxically promoted mitochondrial reactive oxygen species production during ischemia resulting in no recovery of heart function after reperfusion. Limiting the generation of reducing equivalent through modulating carbon substrates availability partially restored the NAD(+)/NADH ratio and protected dominant negative Nox4 hearts from ischemic injury.<br />Conclusions: This study reveals an important role of Nox in cardiac redox regulation and highlights the complexity of developing therapies that affect the intricately connected redox states.
- Subjects :
- Animals
Disease Models, Animal
Energy Metabolism
Glutathione metabolism
Mice
Mice, Knockout
Mitochondria, Heart metabolism
Myocardial Contraction
Myocardial Infarction genetics
Myocardial Infarction pathology
Myocardial Infarction physiopathology
Myocardial Reperfusion Injury genetics
Myocardial Reperfusion Injury pathology
Myocardial Reperfusion Injury physiopathology
Myocardium pathology
NAD metabolism
NADPH Oxidase 4
NADPH Oxidases genetics
Oxidation-Reduction
Reactive Oxygen Species metabolism
Time Factors
Myocardial Infarction enzymology
Myocardial Reperfusion Injury enzymology
Myocardium metabolism
NADPH Oxidases deficiency
Oxidative Stress
Subjects
Details
- Language :
- English
- ISSN :
- 2047-9980
- Volume :
- 3
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of the American Heart Association
- Publication Type :
- Academic Journal
- Accession number :
- 24470522
- Full Text :
- https://doi.org/10.1161/JAHA.113.000555