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 > School of Cardiovascular & Metabolic Health |
| 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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