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Right-ventricular failure is associated with increased mitochondrial complex II activity and production of reactive oxygen species.
- Source :
-
Cardiovascular research [Cardiovasc Res] 2007 Sep 01; Vol. 75 (4), pp. 770-81. Date of Electronic Publication: 2007 May 17. - Publication Year :
- 2007
-
Abstract
- Objective: Reactive oxygen species (ROS) have been implicated in the progression of ventricular hypertrophy to congestive heart failure. However, the source of increased oxidative stress in cardiomyocytes remains unclear.<br />Methods: Here we examined NADPH oxidase and mitochondria as sources of ventricular ROS production in a rat model of right-ventricular (RV) failure (CHF) induced by pulmonary arterial hypertension (PAH).<br />Results: Western analysis showed increased expression of the catalytic subunit gp91(phox) of NADPH oxidase as well as its activator Rac1 in RV in CHF compared to non-failing myocardium (CON). In addition, analysis of mitochondrial respiratory chain complexes showed a selective increase in the expression of Complex II subunit B. Using lucigenin chemiluminescence, tissue homogenates showed increased NADPH oxidase and Complex II-dependent ROS production in failing RV, with no increase in the left ventricle. Functional analyses of isolated RV mitochondria showed an increase in Complex II activity as well as Complex II-associated ROS production in CHF vs CON. An increase in the reduction state of the mitochondrial Coenzyme Q in failing RV, together with increased expression of hypoxia-inducible factor 1 alpha, indicated conditions in CHF that strongly favor ROS production by mitochondria. Reduced ROS-scavenging capacity was indicated by decreased mRNA levels of superoxide dismutases. Oxidative stress in failing RV was indicated by a two-fold increase in the level of phospho-p38 mitogen-activated protein kinase and by immunohistochemical evidence of extensive protein nitration.<br />Conclusions: These data show that the development of PAH-induced RV heart failure is associated with an increased capacity for ROS production by NADPH oxidase as well as mitochondria. The selective increase in expression and activity of mitochondrial Complex II may be particularly important for ventricular ROS production in heart failure.
- Subjects :
- Animals
Biomarkers analysis
Biomechanical Phenomena
Heart Ventricles
Hypoxia-Inducible Factor 1, alpha Subunit analysis
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
Luminescence
Male
Membrane Glycoproteins analysis
Microscopy, Fluorescence
Mitochondria, Heart ultrastructure
Monocrotaline
Myocardium metabolism
Myocardium ultrastructure
NADPH Oxidase 2
NADPH Oxidases analysis
NADPH Oxidases metabolism
Oxidative Stress
Rats
Rats, Wistar
Reverse Transcriptase Polymerase Chain Reaction
Ubiquinone metabolism
Ventricular Dysfunction, Right pathology
rac1 GTP-Binding Protein analysis
Electron Transport Complex II metabolism
Mitochondria, Heart metabolism
Reactive Oxygen Species metabolism
Ventricular Dysfunction, Right metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0008-6363
- Volume :
- 75
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cardiovascular research
- Publication Type :
- Academic Journal
- Accession number :
- 17582388
- Full Text :
- https://doi.org/10.1016/j.cardiores.2007.05.012