Right-ventricular failure is associated with increased mitochondrial complex II activity and production of reactive oxygen species

Everaldo M. Redout, Marijke J. Wagner, Marian J. Zuidwijk, Christa Boer, René J.P. Musters, Cornelis van Hardeveld, Walter J. Paulus, Warner S. Simonides*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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. 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). Results: Western analysis showed increased expression of the catalytic subunit gp91phox 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 1α, 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. 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.

Original languageEnglish
Pages (from-to)770-781
Number of pages12
JournalCardiovascular Research
Volume75
Issue number4
DOIs
Publication statusPublished - 1 Sep 2007

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