Reactive oxygen species as therapeutic targets in pulmonary hypertension

Abstract

Pulmonary hypertension (PH) is characterized by a progressive elevation of pulmonary arterial pressure due to alterations of both pulmonary vascular structure and function. This disease is rare but life-threatening, leading to the development of right heart failure. Current PH treatments, designed to target altered pulmonary vascular reactivity, include vasodilating prostanoids, phosphodiesterase-5 inhibitors and endothelin-1 receptor antagonists. Although managing to slow the progression of the disease, these molecules still do not cure PH. More effective treatments need to be developed, and novel therapeutic strategies, targeting in particular vascular remodelling, are currently under investigation. Reactive oxygen species (ROS) are important physiological messengers in vascular cells. In addition to atherosclerosis and other systemic vascular diseases, emerging evidence also support a role of ROS in PH pathogenesis. ROS production is increased in animal models of PH, associated with NADPH oxidases increased expression, in particular of several Nox enzymes thought to be the major source of ROS in the pulmonary vasculature. These increases have also been observed in vitro and in vivo in humans. Moreover, several studies have shown either the deleterious effect of agents promoting ROS generation on pulmonary vasculature or, conversely, the beneficial effect of antioxidant agents in animal models of PH. In these studies, ROS production has been directly linked to pulmonary vascular remodelling, endothelial dysfunction, altered vasoconstrictive responses, inflammation and modifications of the extracellular matrix, all important features of PH pathophysiology. Altogether, these findings indicate that ROS are interesting therapeutic targets in PH. Blockade of ROS-dependent signalling pathways, or disruption of sources of ROS in the pulmonary vasculature, targeting in particular Nox enzymes, represent promising new therapeutic strategies in this disease.

Regulation of Cellular Communication by Signaling Microdomains in the Blood Vessel Wall

“…Additionally, the increased ROS production has been shown to be involved in VSMC proliferation and endothelial dysfunction (Freund-Michel et al, 2013). Interestingly, in a model of monocrotalininduced pulmonary hypertension, the expression of the gene coding the ClC-3 channels was upregulated in rat pulmonary arteries and cultured canine PASMCs (Dai et al, 2005b).…”

Ranolazine Reduces Remodeling of the Right Ventricle and Provoked Arrhythmias in Rats with Pulmonary Hypertension

“…Although the left and right ventricles have notable and well defined differences (i.e., structural, functional, electrical, and embryological), common mechanisms such as ischemia, Ca 21 overload, oxidative stress, and fibrosis are implicated in the pathology of both left-and right-sided heart failure (Bogaard et al, 2009;Borgdorff et al, 2013;Simon, 2013;Toischer et al, 2013). Pathologic processes that are known to increase late I Na (Voelkel et al, 2012;Freund-Michel et al, 2013;Shryock et al, 2013;Toischer et al, 2013) are also implicated in the progression of RV failure in PAH (Voelkel et al, 2012;FreundMichel et al, 2013;Shryock et al, 2013;Toischer et al, 2013). It was recently reported that RAN reduced RV mass, improved RV performance, and increased exercise capacity in 10 patients with World Health Organization group 1 PAH and symptoms of angina (Shah et al, 2012).…”

Selective depletion of vascular EC-SOD augments chronic hypoxic pulmonary hypertension

“…The currently available therapies for PH have not adequately improved patient outcomes; therefore, a better understanding of the mechanisms underlying the development of PH is necessary to develop effective therapeutic approaches (18,26,29). Oxidative stress and reactive oxygen species (ROS) signaling are now recognized to have a critical role in the pathogenesis of human PH and animal models of PH (2,7,8,15). This area of investigation has important translational implications since antioxidant treatments interrupt multiple pathological signaling pathways, but it is complicated by the observations that low levels of ROS are essential to normal cell signaling, and the reactions of ROS are highly compartmentalized.…”