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

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

doi:10.1016/j.cardiores.2007.05.012

Cited by 158 publications

(148 citation statements)

References 52 publications

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“…Interestingly, only complex I subunits were up-regulated during muscle differentiation ( Figure 7A). The discrepancy in expression levels of mETC complex subunits has been reported previously [37,38] and is consistent with our results.…”

Section: Discussionsupporting

confidence: 93%

Mitochondrial H2O2 generated from electron transport chain complex I stimulates muscle differentiation

et al. 2011

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Mitochondrial reactive oxygen species (mROS) have been considered detrimental to cells. However, their physiological roles as signaling mediators have not been thoroughly explored. Here, we investigated whether mROS generated from mitochondrial electron transport chain (mETC) complex I stimulated muscle differentiation. Our results showed that the quantity of mROS was increased and that manganese superoxide dismutase (MnSOD) was induced via NF-κB activation during muscle differentiation. Mitochondria-targeted antioxidants (MitoQ and MitoTEMPOL) and mitochondria-targeted catalase decreased mROS quantity and suppressed muscle differentiation without affecting the amount of ATP. Mitochondrial alterations, including the induction of mitochondrial transcription factor A and an increase in the number and size of mitochondria, and functional activations were observed during muscle differentiation. In particular, increased expression levels of mETC complex I subunits and a higher activity of complex I than other complexes were observed. Rotenone, an inhibitor of mETC complex I, decreased the mitochondrial NADH/NAD + ratio and mROS levels during muscle differentiation. The inhibition of complex I using small interfering RNAs and rotenone reduced mROS levels, suppressed muscle differentiation, and depleted ATP levels with a concomitant increase in glycolysis. From these results, we conclude that complex I-derived O 2 · − , produced through reverse electron transport due to enhanced metabolism and a high activity of complex I, was dismutated into H 2 O 2 by MnSOD induced via NF-κB activation and that the dismutated mH 2 O 2 stimulated muscle differentiation as a signaling messenger.

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Section: Discussionsupporting

confidence: 93%

Mitochondrial H2O2 generated from electron transport chain complex I stimulates muscle differentiation

et al. 2011

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“…Although there are conflicting data regarding the relative susceptibility of immature hearts to IR injury relative to mature hearts, our data demonstrate the key role of ROS in myocardial apoptosis and dysfunction in neonates. A similar role for ROS in IR injury has been reported in adults (31).…”

Section: Discussionsupporting

confidence: 80%

Impact of N-Acetylcysteine on Neonatal Cardiomyocyte Ischemia-Reperfusion Injury

2011

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ABSTRACT:Reactive oxygen species (ROS) are hypothesized to play a key role in myocardial ischemia-reperfusion (IR) injury after cardiopulmonary bypass in children. Clinical studies in adults and several animal models suggest that myocardial IR injury involves cardiomyocyte apoptosis and necrosis. This study investigated a potential relationship between IR-induced ROS production and neonatal cardiomyocyte apoptosis using both in vitro and ex vivo techniques. For in vitro experiments, embryonic rat cardiomyocytes (H9c2 cells) exposed to hypoxia-reoxygenation (HR) showed a timedependent increase in gp91 phox (a marker for ROS production by NADPH oxidases), caspase-3 (a key mediator of apoptosis) expression, and a decrease in the glutathione redox ratio. N-acetylcysteine (NAC; 0.25-2 mM), a potent antioxidant, decreased gp91 phox and caspase-3 expression, inhibited apoptosis and restored the glutathione redox ratio. M yocardial ischemia-reperfusion (IR) injury associatedwith cardiopulmonary bypass and cardioplegic arrest contributes to adverse outcomes after cardiac surgery. The pathogenesis of IR injury is complex, but reactive oxygen species (ROS) generated during IR are thought to play a pivotal role leading to membrane lipid peroxidation, protein denaturation, and DNA modification, all of which may result in irreversible myocyte injury and cell death. Oxygen free radicals are cytotoxic molecules generated during reperfusion and/or reoxygenation of a previously hypoxic tissue bed. The cell damage induced by ROS can also initiate a local inflammatory response, which leads to further oxidant stressmediated tissue damage (1).Several studies have suggested that ROS are involved in the pathogenesis of perinatal asphyxia (2). Neonates, especially those born prematurely, are particularly vulnerable to ROSmediated tissue damage due, in part, to their immature native antioxidant system (3,4). Similarly, myocardial IR injury seems to be a more clinically significant problem in infants after cardiac surgery compared with adults (5-7). Several ROS-producing systems have been identified in many cell types. NADPH oxidase is reported to be a primary source of ROS production in cardiac tissue, and gp91 phox is responsible for the catalytic activity of NADPH oxidase (8,9). Increased ROS induce apoptosis in cardiomyocytes. Caspase-3 protein is a member of the cysteine-aspartic acid protease family that has been identified as being a key mediator of apoptosis in mammalian cells (10,11).N-acetylcysteine (NAC) is a thiol-containing molecule that acts as a free radical scavenger. In addition, NAC is a glutathione precursor that increases intracellular antioxidant capacity (12). Clinically, NAC is indicated for the treatment of acetaminophen overdose, for the prevention of radiocontrastinduced nephropathy, and as an adjuvant in respiratory conditions with excessive and/or thick mucus production. However, there are contradictory reports on the effects of NAC in clinical (13,14) and animal studies (15-17) of myocardial IR injury. Furthe...

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“…This was corroborated by a recent study (28) of PAH in rats in which we detected increased oxidative stress in cardiomyocytes of the failing RV. In this study, NADPH oxidase and mitochondria were identified as sources of the increase in ROS production.…”

supporting

confidence: 90%

“…In this study, NADPH oxidase and mitochondria were identified as sources of the increase in ROS production. These changes were specific to the overloaded RV, since they were not observed in the left ventricles (LVs) of the same hearts (28). The oxidative stress may at least in part account for the activation of proapoptotic pathways found in the failing RV in PAH (2) but may also account for other aspects of pathological remodeling.…”

mentioning

confidence: 99%

Antioxidant treatment attenuates pulmonary arterial hypertension-induced heart failure

Redout

Toorn²,

Zuidwijk

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

108

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have been implicated in the development of pathological ventricular hypertrophy and the ensuing contractile dysfunction. Using the rat monocrotaline (MCT) model of pulmonary arterial hypertension (PAH), we recently reported oxidative stress in the failing right ventricle (RV) with no such stress in the left ventricle of the same hearts. We used the antioxidant EUK-134 to assess the role of ROS in the pathological remodeling and dysfunction of the RV. PAH was induced by an injection of MCT (80 mg/kg, day 0), treatment with EUK-134 (25 mg/kg, once every 2 days) of control and MCT-injected animals [congestive heart failure (CHF) group] was started on day 10, and animals were analyzed on day 22. EUK-134 treatment of the CHF group attenuated cardiomyocyte hypertrophy and associated changes in mRNA expression (myosin heavy chain-␤ and deiodinase type 3). It also reduced RV oxidative stress and proapoptotic signaling and prevented interstitial fibrosis. Cardiac MRI showed that ROS scavenging did not affect the 37% increase in end-diastolic volume of the RV in the CHF relative to the control group, but the threefold increase in end-systolic volume was reduced by 42% in the EUK-134-treated CHF group. The improved systolic function was confirmed using echocardiography by an assessment of tricuspid annular plane systolic excursion. These data indicate an important role of ROS in RV cardiomyocyte hypertrophy and contractile dysfunction due to PAH and show the potential of EUK-class antioxidants as complementary therapeutics in the treatment of RV dysfunction in PAH. right ventricle; fibrosis; monocrotaline PULMONARY ARTERIAL HYPERTENSION (PAH) due to increased pulmonary vascular resistance causes pressure overload of the right ventricle (RV), which, in turn, leads to RV hypertrophy. This response is aimed at normalizing wall stress and may be successfully compensatory, but at higher levels of PAH, pathological remodeling of the RV progresses to dilation and failure (27). RV failure is a principal secondary cause of morbidity and mortality in patients suffering from PAH (20), and the degree of RV remodeling is predictive of patient outcome (38).A previous study (9) in animal models of PAH has suggested a role for ROS in pathological RV remodeling. This was corroborated by a recent study (28) of PAH in rats in which we detected increased oxidative stress in cardiomyocytes of the failing RV. In this study, NADPH oxidase and mitochondria were identified as sources of the increase in ROS production. These changes were specific to the overloaded RV, since they were not observed in the left ventricles (LVs) of the same hearts (28). The oxidative stress may at least in part account for the activation of proapoptotic pathways found in the failing RV in PAH (2) but may also account for other aspects of pathological remodeling. An in vitro study (33) has shown that ROS may act as signaling molecules driving cardiomyocyte hypertrophy. A study (34) of LV remodeling has shown that high cellular ROS levels activate matrix remodeling and i...

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

Cited by 158 publications

References 52 publications

Mitochondrial H2O2 generated from electron transport chain complex I stimulates muscle differentiation

Mitochondrial H2O2 generated from electron transport chain complex I stimulates muscle differentiation

Impact of N-Acetylcysteine on Neonatal Cardiomyocyte Ischemia-Reperfusion Injury

Antioxidant treatment attenuates pulmonary arterial hypertension-induced heart failure

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