Impact of the mitochondria-targeted antioxidant MitoQ on hypoxia-induced pulmonary hypertension

Pak, Oleg; Scheibe, Susan; Esfandiary, Azadeh; Gierhardt, Mareike; Sydykov, Akylbek; Logan, Angela; Fysikopoulos, Athanasios; Veit, Florian; Hecker, Matthias; Kroschel, Florian; Quanz, Karin; Erb, Alexandra; Schäfer, Karl; Fassbinder, Mirja; Alebrahimdehkordi, Nasim; Ghofrani, Hossein Ardeschir; Schermuly, Ralph T.; Brandes, Ralf P.; Seeger, Werner; Murphy, Michael P.; Weißmann, Norbert; Sommer, Natascha

doi:10.1183/13993003.01024-2017

Cited by 75 publications

(68 citation statements)

References 46 publications

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“…The acute and chronic responses of the pulmonary vasculature to hypoxia have hitherto been assumed to involve similar primary mechanisms and to share regulatory components. However, our data point toward different signaling pathways operating in the two conditions and thus support previous studies that demonstrated a different mechanism of acute HPV and chronic hypoxia-induced PH (5,30,36). Confusingly, previous studies have implicated directionally opposite changes in mitochondrial ROS in chronic hypoxia showing both an increase (28) and a decrease in mitochondrial ROS (37) affecting PASMC proliferation and pulmonary vascular remodeling (38,39).…”

Section: Fig 5 Integration Of Present Findings Into Current Conceptsupporting

confidence: 88%

“…There are also contradictory reports on the effects of mitochondrial ROS on HIF-1, which is a major driver for the development of chronic hypoxia-induced PH (39), with some authors finding evidence of its stabilization by ROS (28,40), while others found no such effect (41). Recently, we found evidence for a decrease in PASMC ROS levels in chronic as opposed to acute hypoxia (36). The fact that AOX did not inhibit chronic hypoxia-induced PH, nor interfere with hypoxiainduced stabilization of HIF-1, may help resolve these discordant findings, recasting the acute and chronic effects of hypoxia in lungs as two fundamentally different processes.…”

Section: Fig 5 Integration Of Present Findings Into Current Conceptmentioning

confidence: 65%

“…Quantification of PH was performed as described (30). Measurement of transthoracic echocardiography was performed in the mice before measurement of invasive hemodynamics using a Vevo2100 highresolution imaging system equipped with a 40-MHz transducer (VisualSonics, Toronto, Canada) as described previously (5,36).…”

Section: Right Ventricular Hemodynamics and Morphometry And Vascular mentioning

confidence: 99%

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Bypassing mitochondrial complex III using alternative oxidase inhibits acute pulmonary oxygen sensing

et al. 2020

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Mitochondria play an important role in sensing both acute and chronic hypoxia in the pulmonary vasculature, but their primary oxygen-sensing mechanism and contribution to stabilization of the hypoxia-inducible factor (HIF) remains elusive. Alteration of the mitochondrial electron flux and increased superoxide release from complex III has been proposed as an essential trigger for hypoxic pulmonary vasoconstriction (HPV). We used mice expressing a tunicate alternative oxidase, AOX, which maintains electron flux when respiratory complexes III and/or IV are inhibited. Respiratory restoration by AOX prevented acute HPV and hypoxic responses of pulmonary arterial smooth muscle cells (PASMC), acute hypoxia-induced redox changes of NADH and cytochrome c, and superoxide production. In contrast, AOX did not affect the development of chronic hypoxia-induced pulmonary hypertension and HIF-1α stabilization. These results indicate that distal inhibition of the mitochondrial electron transport chain in PASMC is an essential initial step for acute but not chronic oxygen sensing.

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Section: Fig 5 Integration Of Present Findings Into Current Conceptsupporting

confidence: 88%

Section: Fig 5 Integration Of Present Findings Into Current Conceptmentioning

confidence: 65%

Section: Right Ventricular Hemodynamics and Morphometry And Vascular mentioning

confidence: 99%

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Bypassing mitochondrial complex III using alternative oxidase inhibits acute pulmonary oxygen sensing

et al. 2020

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“…Interestingly, a divergent regulation of ROS production by PASMCs in acute and chronic hypoxia was previously reported with a significant decrease of ROS production upon acute exposure and a robust increase in ROS levels after chronic exposure [27]. Although additional work is needed to reconcile these discrepant experimental results, PAK et al [14] have brought to light new evidence of the mutual relationship between hypoxia and ROS, fuelling the continuing debate surrounding redox events in pulmonary oxygen sensing. Interesting related questions remain.…”

mentioning

confidence: 86%

“…In their study, PAK et al [14] investigated the open question whether ROS are decreased or increased during acute and chronic hypoxia in the pulmonary vasculature and RV. Using complementary methods, the authors first documented changes in the redox state of mouse PASMCs during acute hypoxia (1% O 2 for 5 min).…”

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confidence: 99%

The ROS controversy in hypoxic pulmonary hypertension revisited

Bonnet

Boucherat

2018

Eur Respir J

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@ERSpublicationsA study published in the ERJ investigates the role of superoxide in adaptation of the pulmonary vasculature to chronic hypoxia and adaptation of the right ventricle to increased afterload http://ow.ly/Dj9Q30iwO8RCite this article as: Bonnet S, Boucherat O. The ROS controversy in hypoxic pulmonary hypertension revisited. Eur Respir J 2018; 51: 1800276 [https://doi.org/10.1183/13993003.00276-2018.Hypoxic pulmonary vasoconstriction (HPV) is a local and adaptive response to alveolar hypoxia causing constriction of small pulmonary arteries, thereby reducing perfusion to underventilated alveoli. However, in pathological conditions characterised by global and persistent hypoxia, such as chronic obstructive pulmonary disease (COPD), this physiological mechanism that normally serves to optimise ventilationperfusion matching become damaging, promoting sustained pulmonary vasoconstriction and vascular remodelling [1]. These structural changes are accompanied by a gradual increase of pulmonary arterial pressure, ultimately leading to right ventricular (RV) hypertrophy and failure. Although there is a global consensus amongst scientists that elevation of the intracellular calcium concentration plays a critical role in producing HPV, the precise underlying mechanisms (e.g. nature of the oxygen sensor, direction of changes in reactive oxygen species (ROS) as well as how ROS production affects the activity of calcium channels) and even the cell type involved remain a subject of ongoing debate [2][3][4].Numerous studies have pinpointed the critical implication of ROS in HPV, but controversy remains regarding levels of ROS that mediate HPV [2,5]. Due, at least in part, to the broad range of chemically distinct ROS, their highly reactive nature, as well as differing methods of quantification and models, conflicting results have been reported establishing two partly opposing models. In the first model so-called "redox hypothesis of HPV", the mitochondrial electron transport chain (ETC) senses hypoxia and decreases ROS production (ROS being produced as an inevitable byproduct of oxidative phosphorylation) causing intracellular calcium influx secondary to redox-sensitive potassium channels inhibition [6, 7]. In support of this, hypoxia and proximal ETC inhibitors have been found to suppress the production of activated O 2 species and increase HPV in endothelium-denuded rings of distal pulmonary arteries [8] as well as isolated perfused rat lungs [6]. This model is challenged by the "ROS hypothesis", which proposes that hypoxia increases mitochondrial ROS generation mediating elevation of intracellular calcium concentration [9][10][11]. This theory is strengthened by studies showing that antioxidants such as catalase and glutathione peroxidase attenuated the HPV response [12] and exogenous H 2 O 2 induces contraction in cultured pulmonary artery smooth muscle cells (PASMCs) and HPV in isolated lungs [13].

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