Serotonin signaling through the 5-HT 1B receptor and NADPH oxidase 1 in pulmonary arterial hypertension

Katie Y. Hood, Kirsty M. Mair, Adam P. Harvey, Augusto C. Montezano, Rhian M. Touyz, Margaret R. MacLean

Research output: Contribution to journalArticle

14 Citations (Scopus)

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 hypothesize that in PASMCs, serotonin induces oxidative stress through NADPH-oxidase-derived ROS generation and reduced Nrf-2 (nuclear factor [erythroid-derived 2]-like 2) antioxidant 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-HT 1B 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 female mice, a model of pulmonary hypertension. We confirmed thatserotonin increased superoxide and hydrogen peroxide production in these cells. For the first time, we show that serotonin increased oxidized protein tyrosine phosphatases and hyperoxidized peroxiredoxin and decreased Nrf-2 and catalase activity in hPASMCs. ROS generation was exaggerated and dependent on cellular Src-related kinase, 5-HT 1B receptor, and the serotonin transporter in human pulmonary artery smooth muscle cells from PAH subjects. Proliferation and extracellular matrix remodeling were exaggerated in human pulmonary artery smooth muscle cells from PAH subjects and dependent on 5-HT 1B receptor signaling and Nox1, confirmed in PASMCs from Nox1 -/- mice. In serotonin transporter overexpressing mice, SB216641, a 5-HT 1B receptor antagonist, prevented development of pulmonary hypertension in a ROS-dependent manner. Conclusions - Serotonin can induce cellular Src-related kinase-regulated Nox1-induced ROS and Nrf-2 dysregulation, contributing to increased post-translational oxidative modification of proteins and activation of redox-sensitive signaling pathways in hPASMCs, associated with mitogenic responses. 5-HT 1B receptors contribute to experimental pulmonary hypertension by inducing lung ROS production. Our results suggest that 5-HT 1B receptor-dependent cellular Src-related kinase-Nox1-pathways contribute to vascular remodeling in PAH.

LanguageEnglish
Pages1361-1370
Number of pages10
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume37
Issue number7
DOIs
Publication statusPublished - 1 Jul 2017

Fingerprint

Receptor, Serotonin, 5-HT1B
Pulmonary Hypertension
Serotonin
Reactive Oxygen Species
src-Family Kinases
Serotonin Plasma Membrane Transport Proteins
Pulmonary Artery
Smooth Muscle Myocytes
Peroxiredoxins
Protein Tyrosine Phosphatases
NADPH oxidase 1
NADPH Oxidase
Vascular System Injuries
Post Translational Protein Processing
Superoxides
Catalase
Hydrogen Peroxide
Oxidation-Reduction
Extracellular Matrix
Oxidative Stress

Keywords

  • pulmonary hypertension
  • models, animal
  • NADPH oxidase
  • receptor, serotonin, 5-HT
  • serotonin

Cite this

@article{2c28cab47a344cc4afd2d850677e7522,
title = "Serotonin signaling through the 5-HT 1B receptor and NADPH oxidase 1 in pulmonary arterial hypertension",
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 hypothesize that in PASMCs, serotonin induces oxidative stress through NADPH-oxidase-derived ROS generation and reduced Nrf-2 (nuclear factor [erythroid-derived 2]-like 2) antioxidant 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-HT 1B 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 female mice, a model of pulmonary hypertension. We confirmed thatserotonin increased superoxide and hydrogen peroxide production in these cells. For the first time, we show that serotonin increased oxidized protein tyrosine phosphatases and hyperoxidized peroxiredoxin and decreased Nrf-2 and catalase activity in hPASMCs. ROS generation was exaggerated and dependent on cellular Src-related kinase, 5-HT 1B receptor, and the serotonin transporter in human pulmonary artery smooth muscle cells from PAH subjects. Proliferation and extracellular matrix remodeling were exaggerated in human pulmonary artery smooth muscle cells from PAH subjects and dependent on 5-HT 1B receptor signaling and Nox1, confirmed in PASMCs from Nox1 -/- mice. In serotonin transporter overexpressing mice, SB216641, a 5-HT 1B receptor antagonist, prevented development of pulmonary hypertension in a ROS-dependent manner. Conclusions - Serotonin can induce cellular Src-related kinase-regulated Nox1-induced ROS and Nrf-2 dysregulation, contributing to increased post-translational oxidative modification of proteins and activation of redox-sensitive signaling pathways in hPASMCs, associated with mitogenic responses. 5-HT 1B receptors contribute to experimental pulmonary hypertension by inducing lung ROS production. Our results suggest that 5-HT 1B receptor-dependent cellular Src-related kinase-Nox1-pathways contribute to vascular remodeling in PAH.",
keywords = "pulmonary hypertension, models, animal, NADPH oxidase, receptor, serotonin, 5-HT, serotonin",
author = "Hood, {Katie Y.} and Mair, {Kirsty M.} and Harvey, {Adam P.} and Montezano, {Augusto C.} and Touyz, {Rhian M.} and MacLean, {Margaret R.}",
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Serotonin signaling through the 5-HT 1B receptor and NADPH oxidase 1 in pulmonary arterial hypertension. / Hood, Katie Y.; Mair, Kirsty M.; Harvey, Adam P.; Montezano, Augusto C.; Touyz, Rhian M.; MacLean, Margaret R.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 37, No. 7, 01.07.2017, p. 1361-1370.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Serotonin signaling through the 5-HT 1B receptor and NADPH oxidase 1 in pulmonary arterial hypertension

AU - Hood, Katie Y.

AU - Mair, Kirsty M.

AU - Harvey, Adam P.

AU - Montezano, Augusto C.

AU - Touyz, Rhian M.

AU - MacLean, Margaret R.

PY - 2017/7/1

Y1 - 2017/7/1

N2 - 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 hypothesize that in PASMCs, serotonin induces oxidative stress through NADPH-oxidase-derived ROS generation and reduced Nrf-2 (nuclear factor [erythroid-derived 2]-like 2) antioxidant 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-HT 1B 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 female mice, a model of pulmonary hypertension. We confirmed thatserotonin increased superoxide and hydrogen peroxide production in these cells. For the first time, we show that serotonin increased oxidized protein tyrosine phosphatases and hyperoxidized peroxiredoxin and decreased Nrf-2 and catalase activity in hPASMCs. ROS generation was exaggerated and dependent on cellular Src-related kinase, 5-HT 1B receptor, and the serotonin transporter in human pulmonary artery smooth muscle cells from PAH subjects. Proliferation and extracellular matrix remodeling were exaggerated in human pulmonary artery smooth muscle cells from PAH subjects and dependent on 5-HT 1B receptor signaling and Nox1, confirmed in PASMCs from Nox1 -/- mice. In serotonin transporter overexpressing mice, SB216641, a 5-HT 1B receptor antagonist, prevented development of pulmonary hypertension in a ROS-dependent manner. Conclusions - Serotonin can induce cellular Src-related kinase-regulated Nox1-induced ROS and Nrf-2 dysregulation, contributing to increased post-translational oxidative modification of proteins and activation of redox-sensitive signaling pathways in hPASMCs, associated with mitogenic responses. 5-HT 1B receptors contribute to experimental pulmonary hypertension by inducing lung ROS production. Our results suggest that 5-HT 1B receptor-dependent cellular Src-related kinase-Nox1-pathways contribute to vascular remodeling in PAH.

AB - 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 hypothesize that in PASMCs, serotonin induces oxidative stress through NADPH-oxidase-derived ROS generation and reduced Nrf-2 (nuclear factor [erythroid-derived 2]-like 2) antioxidant 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-HT 1B 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 female mice, a model of pulmonary hypertension. We confirmed thatserotonin increased superoxide and hydrogen peroxide production in these cells. For the first time, we show that serotonin increased oxidized protein tyrosine phosphatases and hyperoxidized peroxiredoxin and decreased Nrf-2 and catalase activity in hPASMCs. ROS generation was exaggerated and dependent on cellular Src-related kinase, 5-HT 1B receptor, and the serotonin transporter in human pulmonary artery smooth muscle cells from PAH subjects. Proliferation and extracellular matrix remodeling were exaggerated in human pulmonary artery smooth muscle cells from PAH subjects and dependent on 5-HT 1B receptor signaling and Nox1, confirmed in PASMCs from Nox1 -/- mice. In serotonin transporter overexpressing mice, SB216641, a 5-HT 1B receptor antagonist, prevented development of pulmonary hypertension in a ROS-dependent manner. Conclusions - Serotonin can induce cellular Src-related kinase-regulated Nox1-induced ROS and Nrf-2 dysregulation, contributing to increased post-translational oxidative modification of proteins and activation of redox-sensitive signaling pathways in hPASMCs, associated with mitogenic responses. 5-HT 1B receptors contribute to experimental pulmonary hypertension by inducing lung ROS production. Our results suggest that 5-HT 1B receptor-dependent cellular Src-related kinase-Nox1-pathways contribute to vascular remodeling in PAH.

KW - pulmonary hypertension

KW - models, animal

KW - NADPH oxidase

KW - receptor, serotonin, 5-HT

KW - serotonin

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UR - https://www.ahajournals.org/journal/atvb

U2 - 10.1161/ATVBAHA.116.308929

DO - 10.1161/ATVBAHA.116.308929

M3 - Article

VL - 37

SP - 1361

EP - 1370

JO - Arteriosclerosis Thrombosis, and Vascular Biology

T2 - Arteriosclerosis Thrombosis, and Vascular Biology

JF - Arteriosclerosis Thrombosis, and Vascular Biology

SN - 1079-5642

IS - 7

ER -