title: Oxidative and nitrosative signalling in pulmonary arterial hypertension - Implications for development of novel therapies.
abstract: Pulmonary arterial hypertension (PAH) is a syndrome characterised by an increase in pulmonary vascular resistance. This results in elevated resting pulmonary artery pressure and leads to progressive right ventricular (RV) failure, secondary to increased afterload. Although initially thought to be a disease driven primarily by endothelial dysfunction with a resultant vasoconstrictor versus vasodilator imbalance, it has become increasingly apparent that the rise in pulmonary vascular resistance that causes RV failure is also attributable to pulmonary vascular remodelling. This inflammatory, hyper-proliferative and anti-apoptotic phenotype is accompanied by a metabolic switch from physiological mitochondrial oxidative phosphorylation to aerobic glycolysis. The molecular pathways triggering this cellular metabolic shift have been the subject of extensive investigation, as their discovery will inevitably lead to new therapeutic targets. Reactive oxygen/nitrogen species (ROS/RNS) including hydrogen peroxide, superoxide and peroxynitrite are second messenger molecules that are involved in functional oxidative and nitrosative modification of proteins. Dysregulation of oxidative signalling caused by an excess of ROS and RNS relative to antioxidants has been heavily implicated in the underlying pathophysiology of PAH and likely participates in this metabolic reprogramming. This review will focus on the role of oxidative signalling and redox reactions to the molecular pathology of PAH. In addition, promising novel therapeutic agents targeting these pathways will be discussed.
authors.affiliation: North Shore Heart Research, Kolling Institute, University of Sydney, St Leonards, NSW, 2065, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hansen
authors.affiliation: Columbia University Medical Centre, New York, USA.
authors.forename: Keyvan-Karimi
authors.initials: KK
authors.lastname: Galougahi
authors.affiliation: Dept of Cardiology, Royal Prince Alfred Hospital, Camperdown, NSW, 2050, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Celermajer
authors.affiliation: North Shore Heart Research, Kolling Institute, University of Sydney, St Leonards, NSW, 2065, Australia.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rasko
authors.affiliation: North Shore Heart Research, Kolling Institute, University of Sydney, St Leonards, NSW, 2065, Australia.
authors.forename: Owen
authors.initials: O
authors.lastname: Tang
authors.affiliation: North Shore Heart Research, Kolling Institute, University of Sydney, St Leonards, NSW, 2065, Australia.
authors.forename: Kristen J
authors.initials: KJ
authors.lastname: Bubb
authors.affiliation: North Shore Heart Research, Kolling Institute, University of Sydney, St Leonards, NSW, 2065, Australia. Electronic address: gemma.figtree@usyd.edu.au.
authors.forename: Gemma
authors.initials: G
authors.lastname: Figtree
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000975:Antioxidants / Q000009:adverse effects / Q000627:therapeutic use*; D062186:Arterial Pressure / Q000187:drug effects*; D015195:Drug Design; D006801:Humans; D006976:Hypertension, Pulmonary / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D058990:Molecular Targeted Therapy; D015538:Nitrosation; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D011651:Pulmonary Artery / Q000187:drug effects* / Q000503:physiopathology; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D000975:Antioxidants; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species
keywords: Endothelial nitric oxide synthase; Glutathionylation; Mitochondrial electron transport chain; NADPH oxidase; Pulmonary arterial hypertension; Reactive oxygen species