The ROS controversy in hypoxic pulmonary hypertension revisited

Abstract

@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].

H2S attenuates endoplasmic reticulum stress in hypoxia-induced pulmonary artery hypertension

“…But the pathogenesis of hypoxic pulmonary hypertension has not been fully understood yet. Overproduction of ROS can result in the progression of pulmonary vascular remodeling [17–19]. H 2 S is an essential small molecule in human physiology.…”

OP2113, a new drug for chronic hypoxia‐induced pulmonary hypertension treatment in rat

“…Although still under debate, CH‐PH has been shown to be associated with a dysregulation of mitochondrial ROS production both in PA and in the heart (Bonnet & Boucherat, 2018; Freund‐Michel et al, 2013, 2014; Pak et al, 2018). In this context, we have evaluated oxidative stress markers in PA and heart from N and CH rats with or without treatment with OP2113 in vivo (Figures 6 and S6).…”

The newborn sheep translational model for pulmonary arterial hypertension of the neonate at high altitude

“…In the first model, the so-called redox hypothesis, 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 channel inhibition. 113,129 In support of this, Michelakis et al demonstrated that hypoxia and ETC inhibitors suppress the production of activated O 2 species and increase the vasoconstriction of ex vivo pulmonary arteries. 130 The second model is challenged by the ROS hypothesis, which proposes that hypoxia increases mitochondrial ROS generation, mediating elevation of intracellular calcium concentration.…”