title: 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.
authors: Laboratoire de Pharmacologie-INSERM U1045, UFR des Sciences Pharmaceutiques, Université Bordeaux Segalen, Case 83, 146 Rue Léo Saignat, 33076 Bordeaux Cedex, France. veronique.michel@u-bordeaux2.fr
authors: Véronique
authors: V
authors: Freund-Michel
authors: Christelle
authors: C
authors: Guibert
authors: Mathilde
authors: M
authors: Dubois
authors: Arnaud
authors: A
authors: Courtois
authors: Roger
authors: R
authors: Marthan
authors: Jean-Pierre
authors: JP
authors: Savineau
authors: Bernard
authors: B
authors: Muller
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D062186:Arterial Pressure / Q000187:drug effects; D018450:Disease Progression; D015195:Drug Design; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D058990:Molecular Targeted Therapy; D019255:NADPH Oxidases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases
keywords: NAPDH oxidases; Nox enzymes; endothelial dysfunction; inflammation; pulmonary hypertension (PH); pulmonary vasculature; reactive oxygen species (ROS); vascular hyperreactivity; vascular remodelling