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

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-HT(1B) and 5-HT(2A) receptors and SERT, receptor sensitivity to Y27632 was restricted to the 5-HT(1B) 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-HT(1B) receptor-stimulated ERK activation and proliferation in vitro by facilitating MEK-ERK interaction.

journal_name

Br J Pharmacol

authors

Mair KM,MacLean MR,Morecroft I,Dempsie Y,Palmer TM

doi

10.1038/bjp.2008.310

subject

Has Abstract

pub_date

2008-10-01 00:00:00

pages

606-16

issue

4

eissn

0007-1188

issn

1476-5381

pii

bjp2008310

journal_volume

155

pub_type

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