Abstract:
BACKGROUND AND PURPOSE:Pulmonary arterial hypertension (PAH, type 1 pulmonary hypertension) has a 3-year survival of ~50% and is in need of new, effective therapies. In PAH, remodelling of the pulmonary artery (PA) increases pulmonary vascular resistance and can result in right heart dysfunction and failure. Genetic mutations can cause PAH but it can also be idiopathic (IPAH). Enhanced contractility and proliferation of PA smooth muscle cells (PASMCs) are key contributors to the pathophysiology of PAH, but the underlying mechanisms are not well understood. EXPERIMENTAL APPROACH:We utilized RNA-sequencing (RNA-seq) of IPAH and control patient-derived PASMCs as an unbiased approach to define differentially expressed (DE) genes that may identify new biology and potential therapeutic targets. KEY RESULTS:Analysis of DE genes for shared gene pathways revealed increases in genes involved in cell proliferation and mitosis and decreases in a variety of gene sets, including response to cytokine signalling. ADGRG6/GPR126, an adhesion G protein-coupled receptor (GPCR), was increased in IPAH-PASMCs compared to control-PASMCs. Increased expression of this GPCR in control-PASMCs decreased their proliferation; siRNA knockdown of ADGRG6/GPR126 in IPAH-PASMCs tended to increase proliferation. CONCLUSION AND IMPLICATIONS:These data provide insights regarding the expression of current and experimental PAH drug targets, GPCRs and GPCR-related genes as potentially new therapeutic targets in PAH-PASMCs. Overall, the findings identify genes and pathways that may contribute to IPAH-PASMC function and suggest that ADGRG6/GPR126 is a novel therapeutic target for IPAH.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Gorr MW,Sriram K,Muthusamy A,Insel PAdoi
10.1111/bph.15074subject
Has Abstractpub_date
2020-08-01 00:00:00pages
3505-3518issue
15eissn
0007-1188issn
1476-5381journal_volume
177pub_type
杂志文章abstract::1. SCA40 (1nM-10 microM), isoprenaline (1-300 nM) and levcromakalim (100 nM-10 microM) each produced concentration-dependent suppression of the spontaneous tone of guinea-pig isolated trachea. Propranolol (1 microM) markedly (approximately 150 fold) antagonized isoprenaline but did not antagonize SCA40. The tracheal r...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1995.tb14918.x
更新日期:1995-01-01 00:00:00
abstract::We have recently shown that in polymorphonuclear leukocytes, 11-keto boswellic acids (KBAs) induce Ca2+ mobilisation and activation of mitogen-activated protein kinases (MAPK). Here we addressed the effects of BAs on central signalling pathways in human platelets and on various platelet functions. We found that beta-B...
journal_title:British journal of pharmacology
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journal_title:British journal of pharmacology
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更新日期:1987-03-01 00:00:00
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journal_title:British journal of pharmacology
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更新日期:1998-12-01 00:00:00
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更新日期:1990-08-01 00:00:00
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更新日期:2000-08-01 00:00:00
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更新日期:1992-04-01 00:00:00
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更新日期:2001-07-01 00:00:00
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pub_type: 传,社论,历史文章
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更新日期:2009-10-01 00:00:00
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