Hood, K. Y., Mair, K. M., Harvey, A. P., Montezano, A. C., Touyz, R. M. and MacLean, M. R. (2017) Serotonin signaling through the 5-HT1B receptor and NADPH oxidase 1 in pulmonary arterial hypertension. Arteriosclerosis, Thrombosis, and Vascular Biology, 37(7), pp. 1361-1370. (doi: 10.1161/ATVBAHA.116.308929) (PMID:28473438) (PMCID:PMC5478178)
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Abstract
Objective: Serotonin can induce human pulmonary artery smooth muscle cell (hPASMC) proliferation through reactive oxygen species (ROS), influencing the development of pulmonary arterial hypertension (PAH). We hypothesise that in PASMCs, serotonin induces oxidative stress through NADPH-oxidase-derived ROS generation and reduced Nrf-2 anti-oxidant systems, promoting vascular injury. Approach and Results: HPASMCs from controls and PAH patients, and PASMCs from Nox1-/- mice, were stimulated with serotonin in the absence/presence of inhibitors of Src kinase, the 5-HT1B receptor and NADPH oxidase 1 (Nox1). Markers of fibrosis were also determined. The pathophysiological significance of our findings was examined in vivo in serotonin transporter overexpressing (SERT+) female mice, a model of pulmonary hypertension (PH). We confirmed serotonin increased superoxide and H2O2 production in these cells. For the first time, we show that serotonin increased oxidized protein tyrosine phosphatases and peroxiredoxin-SO3H and decreased Nrf-2 and catalase activity in hPASMCs. ROS generation was exaggerated, and dependent on c-Src, 5-HT1B receptor and the serotonin transporter in PAH-hPASMCs. Proliferation and extracellular matrix remodeling were exaggerated in PAH-hPASMCs and dependent on 5-HT1B receptor signaling and Nox1, confirmed in PASMCs from Nox1-/- mice. In SERT+ mice, SB216641, a 5-HT1B receptor antagonist, prevented development of PH in a ROS-dependent manner. Conclusions: Serotonin can induce c-Src-regulated Nox1-induced ROS and Nrf-2 dysregulation, contributing to increased post-translational oxidative modification of proteins, activation of redox-sensitive signaling pathways in hPASMCs; associated with mitogenic responses. 5-HT1B receptors contribute to experimental PH by inducing lung ROS production. Our results suggest 5-HT1B receptor-dependent c-Src-Nox1-pathways contribute to vascular remodeling in PAH.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | MacLean, Professor Margaret and Harvey, Dr Adam and Harvey, Dr Katie and Mair, Dr Kirsty and Montezano, Dr Augusto and Touyz, Professor Rhian |
| Authors: | Hood, K. Y., Mair, K. M., Harvey, A. P., Montezano, A. C., Touyz, R. M., and MacLean, M. R. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health |
| Journal Name: | Arteriosclerosis, Thrombosis, and Vascular Biology |
| Publisher: | American Heart Association |
| ISSN: | 1079-5642 |
| ISSN (Online): | 1524-4636 |
| Published Online: | 04 May 2017 |
| Copyright Holders: | Copyright © 2017 The Authors |
| First Published: | First published in Arteriosclerosis, Thrombosis, and Vascular Biology 37(7):1361-1370 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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