期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 155, 期 4, 页码 606-616出版社
WILEY
DOI: 10.1038/bjp.2008.310
关键词
5-HT; pulmonary arterial hypertension; Rho kinase; fibroblast; proliferation
资金
- the British Heart Foundation
- the Biotechnology and Biological Sciences Research Council
- Biotechnology and Biological Sciences Research Council [BB/F005423/1] Funding Source: researchfish
- BBSRC [BB/F005423/1] Funding Source: UKRI
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.
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