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 Pharmacoljournal_title
British journal of pharmacologyauthors
Mair KM,MacLean MR,Morecroft I,Dempsie Y,Palmer TMdoi
10.1038/bjp.2008.310subject
Has Abstractpub_date
2008-10-01 00:00:00pages
606-16issue
4eissn
0007-1188issn
1476-5381pii
bjp2008310journal_volume
155pub_type
杂志文章abstract::A new arylamino-pyridazine gamma-aminobutyric acid (GABA) derivative, SR 42641, has been tested for its ability to antagonize the actions of GABA on mammalian sensory neurones. SR 42641 and bicuculline reversibly decreased GABAA-induced depolarizations and currents recorded intracellularly from dorsal root ganglion ne...
journal_title:British journal of pharmacology
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doi:10.1111/j.1476-5381.1987.tb08958.x
更新日期:1987-02-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Necroptosis is a form of programmed, caspase-independent, cell death, mediated by receptor-interacting protein kinases, RIPK1 and RIPK3, and the mixed lineage kinase domain-like (MLKL). Necroptosis contributes to the pathophysiology of various inflammatory, infectious, and degenerative diseases. ...
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更新日期:1991-06-01 00:00:00
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更新日期:1983-05-01 00:00:00
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更新日期:2005-04-01 00:00:00
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