Selenoprotein P Promotes the Development of Pulmonary Arterial Hypertension
- 7 August 2018
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation
- Vol. 138 (6), 600-623
- https://doi.org/10.1161/circulationaha.117.033113
Abstract
Background: Excessive proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs) are key mechanisms of pulmonary arterial hypertension (PAH). Despite the multiple combination therapy, a considerable number of patients develop severe pulmonary hypertension (PH) because of the lack of diagnostic biomarker and antiproliferative therapies for PASMCs. Methods: Microarray analyses were used to identify a novel therapeutic target for PAH. In vitro experiments, including lung and serum samples from patients with PAH, cultured PAH-PASMCs, and high-throughput screening of 3336 low-molecular-weight compounds, were used for mechanistic study and exploring a novel therapeutic agent. Five genetically modified mouse strains, including PASMC-specific selenoprotein P (SeP) knockout mice and PH model rats, were used to study the role of SeP and therapeutic capacity of the compounds for the development of PH in vivo. Results: Microarray analysis revealed a 32-fold increase in SeP in PAH-PASMCs compared with control PASMCs. SeP is a widely expressed extracellular protein maintaining cellular metabolism. Immunoreactivity of SeP was enhanced in the thickened media of pulmonary arteries in PAH. Serum SeP levels were also elevated in patients with PH compared with controls, and high serum SeP predicted poor outcome. SeP-knockout mice (SeP–/–) exposed to chronic hypoxia showed significantly reduced right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary artery remodeling compared with controls. In contrast, systemic SeP-overexpressing mice showed exacerbation of hypoxia-induced PH. Furthermore, PASMC-specific SeP–/– mice showed reduced hypoxia-induced PH compared with controls, whereas neither liver-specific SeP knockout nor liver-specific SeP-overexpressing mice showed significant differences with controls. Altogether, protein levels of SeP in the lungs were associated with the development of PH. Mechanistic experiments demonstrated that SeP promotes PASMC proliferation and resistance to apoptosis through increased oxidative stress and mitochondrial dysfunction, which were associated with activated hypoxia-inducible factor-1α and dysregulated glutathione metabolism. It is important to note that the high-throughput screening of 3336 compounds identified that sanguinarine, a plant alkaloid with antiproliferative effects, reduced SeP expression and proliferation in PASMCs and ameliorated PH in mice and rats. Conclusions: These results indicate that SeP promotes the development of PH, suggesting that it is a novel biomarker and therapeutic target of the disorder.This publication has 86 references indexed in Scilit:
- Higher Estradiol and Lower Dehydroepiandrosterone-Sulfate Levels Are Associated with Pulmonary Arterial Hypertension in MenAmerican Journal of Respiratory and Critical Care Medicine, 2016
- A global view of pulmonary hypertensionThe Lancet Respiratory Medicine, 2016
- Estrogen Metabolite 16α-Hydroxyestrone Exacerbates Bone Morphogenetic Protein Receptor Type II–Associated Pulmonary Arterial Hypertension Through MicroRNA-29–Mediated Modulation of Cellular MetabolismCirculation, 2016
- Effect of Simvastatin on 5-HT and 5-HTT in a Rat Model of Pulmonary Artery HypertensionCellular Physiology and Biochemistry, 2015
- Pulmonary Hypertension in Obstructive Sleep Apnea: Is it Clinically Significant? a Critical Analysis of the Association and PathophysiologyPulmonary Circulation, 2015
- Obesity‐Related Pulmonary Arterial Hypertension in Rats Correlates with Increased Circulating Inflammatory Cytokines and Lipids and with Oxidant Damage in the Arterial Wall but not with HypoxiaPulmonary Circulation, 2014
- The Genetics of Pulmonary Arterial HypertensionCirculation Research, 2014
- Perspective: Ambient Air Pollution: Inflammatory Response and Effects on the Lung's VasculaturePulmonary Circulation, 2014
- Molecular pathogenesis of pulmonary arterial hypertensionJCI Insight, 2012
- Cellular and Molecular Basis of Pulmonary Arterial HypertensionJournal of the American College of Cardiology, 2009