Hood, K. Y., Montezano, A. C., Morecroft, I., MacLean, M. R. and Touyz, R. M. (2013) Serotonin signaling through Nox1 in human pulmonary artery smooth muscle cells - implications in vascular remodeling in pulmonary arterial hypertension. Hypertension, 62(3 Sup), A264.
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Publisher's URL: http://hyper.ahajournals.org/cgi/content/meeting_abstract/62/3_MeetingAbstracts/A264
Abstract
Serotonin (5HT) and NADPH oxidases (Nox) have been linked to the pathology of pulmonary arterial hypertension (PAH). However, it is unclear whether 5HT plays a role in PAH through Nox-dependent mechanisms. We hypothesised that 5HT through Nox1-induced reactive oxygen species (ROS) induces PASMC damage. Human PASMC primary cultures were stimulated with 5HT (1μM) in the absence/presence of tempol (antioxidant, 10μmol/L), ML171 (Nox1 inhibitor; 1μM), and EHT1864 (Rac1 inhibitor; 100μM). ROS generation was assessed by chemiluminescence. Markers of fibrosis (fibronectin), growth (PCNA), inflammation (TRAIL, DcR2), Nrf2 regulation (Nrf2, BACH1, HO1) and MAPKs activation (ERK1/2 and p38MAPK) were analyzed by immunoblotting. Proliferation was assessed by [3H]-thymidine incorporation in the presence/absence of Nox1 inhibitor. 5HT induced increased in ROS production at 4h of stimulation (224 ± 49% vs vehicle; p<0.05) in PASMC, an effect blocked by tempol, EHT1864 and ML171. Fibronectin (192 ± 26%), PCNA (124 ± 2%), TRAIL (122 ± 4%) and DcR2 (133 ± 2%) protein levels were increased by 5HT in PASMCs (p<0.05, vs vehicle). In addition, 5HT increased phosphorylation of ERK1/2 (169 ± 10%) and p38MAPK (157 ± 15%) (p<0.05, vs vehicle). Levels of Nrf2 and its downstream target, HO-1, were decreased by 5HT stimulation (90 ± 1%; 84 ± 6% respectively vs vehicle 100%, p<0.05). BACH1 expression, a protein that negatively modulates antioxidant regulator Nrf2, was increased by 5HT in PASMCs (153 ± 8% vs vehicle; p<0.05). Nox1, but not Nox2, expression was increased in PASMC after stimulation with 5HT (139 ± 11% vs vehicle, p<0.05). 5HT induced a 3.95±0.39 fold increase in proliferation PASMCs (P<0.05), which was blocked by ML171. In conclusion, Nox1 may play a role in 5HT-induced pro-proliferative, fibrotic and inflammatory responses. These data highlight some molecular mechanisms whereby 5HT may exert deleterious vascular effects in PAH.
Item Type: | Articles |
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Additional Information: | American-Heart-Association High Blood Pressure Research Scientific Sessions, New Orleans, LA, USA, 11-14 Sept 2013. |
Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Montezano, Dr Augusto and Touyz, Professor Rhian |
Authors: | Hood, K. Y., Montezano, A. C., Morecroft, I., MacLean, M. R., and Touyz, R. M. |
College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health |
Journal Name: | Hypertension |
Publisher: | American Heart Association |
ISSN: | 0194-911X |
ISSN (Online): | 1524-4563 |
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