Novel interactions between the 5-HT transporter, 5-HT1B receptors and Rho kinase in vivo and in pulmonary fibroblasts

Mair, K.M., MacLean, M.R., Morecroft, I., Dempsie, Y. and Palmer, T.M. (2008) Novel interactions between the 5-HT transporter, 5-HT1B receptors and Rho kinase in vivo and in pulmonary fibroblasts. British Journal of Pharmacology, 155(4), pp. 606-616. (doi: 10.1038/bjp.2008.310) (PMID:18695640) (PMCID:PMC2579673)

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Abstract

Background and purpose: While the 5-HT and Rho-kinase ( ROCK) pathways have been implicated in the development of pulmonary arterial hypertension (PAH), the nature of any interactions between them remain unclear. This study investigated a role for ROCK in 5-HT-regulated proliferative responses in lung fibroblasts in vivo and in vitro. Experimental approach: PAH was examined in mice over-expressing human 5-HT transporters (SERT+), from which pulmonary artery fibroblasts (PFs) were isolated to assess ROCK expression. In vitro analysis of 5-HT signalling employed CCL39 hamster lung fibroblasts. Key results: ROCK inhibition ablated increased pulmonary remodelling and hypertension observed in SERT+ mice, and ROCK1/2 protein levels were elevated in SERT+ PFs. ROCK inhibition also reduced 5-HT-stimulated proliferation by suppressing MEK-stimulated ERK phosphorylation. While optimal 5-HT-stimulated proliferation required 5-HT1B and 5-HT2A receptors and SERT, receptor sensitivity to Y27632 was restricted to the 5-HT1B receptor. Also, while hypoxia-induced pulmonary vascular remodelling and hypertension were sensitive to Y27632 in WT and SERT+ animals, the proportions sensitive to ROCK inhibition were increased by SERT over-expression. Conclusions and implications: SERT over-expression increased ROCK-dependent pulmonary remodelling in normoxia and hypoxia and SERT over-expression was associated with elevated ROCK1/2 levels. ROCK also potentiated 5-HT1B receptorstimulated ERK activation and proliferation in vitro by facilitating MEK-ERK interaction.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:MacLean, Professor Margaret and Palmer, Dr Timothy and Dempsie, Dr Yvonne and Morecroft, Dr Ian and Mair, Dr Kirsty
Authors: Mair, K.M., MacLean, M.R., Morecroft, I., Dempsie, Y., and Palmer, T.M.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:British Journal of Pharmacology
Publisher:John Wiley & Sons, Inc.
ISSN:0007-1188
ISSN (Online):1476-5381
Published Online:29 January 2009

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
460941The role of endothelial tryptophan hydroxylase in pulmonary vascular remodelling: an integrated approachMargaret MacLeanBiotechnology and Biological Sciences Research Council (BBSRC)BB/F005423/1Institute of Cardiovascular and Medical Sciences