RGD Reference Report - TRAM-34 attenuates hypoxia induced pulmonary artery smooth muscle cell proliferation. - Rat Genome Database

RGD Reference Report - TRAM-34 attenuates hypoxia induced pulmonary artery smooth muscle cell proliferation. - Rat Genome Database

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TRAM-34 attenuates hypoxia induced pulmonary artery smooth muscle cell proliferation.
Authors:	Guo, S-J Wang, T Jia, L-Q Li, D-D Shen, Y-C Xu, D Wen, F-Q
Citation:	Guo SJ, etal., Eur Rev Med Pharmacol Sci. 2015 Sep;19(18):3515-21.
RGD ID:	401794572
Pubmed:	PMID:26439051 (View Abstract at PubMed)
OBJECTIVE: Hypoxia is an important risk factor for pulmonary arterial remodeling in pulmonary arterial hypertension (PAH). Pulmonary artery smooth muscle cell (PASMC) proliferation is a major contributor to pulmonary vascular remodeling. The intermediate-conductance Ca2+-activated K+ channel (Kca3.1) has been implicated in disease states characterized by excessive cell proliferation, but its role in hypoxia-induced PASMC proliferation is unknown. In the present study, we sought to investigate the effect of TRAM-34 (triarylmethane-34), a selective blocker of Kca3.1, on hypoxia-induced PASMC proliferation and underlying mechanisms. METHODS: PASMC was exposed to hypoxia (2% O2) for 24 hours, cell proliferation and cell cycle analysis were measured by cell counting kit (CCK-8) and flow cytometry. Cell signaling were examined using Quantitative real-time PCR and Western blotting. RESULTS: CCK8 results showed that TRAM-34 reduced PASMC proliferation under hypoxia. Flow cytometry revealed that TRAM-34 inhibited PASMC proliferation by G0/G1 arrest. Quantitative real-time PCR and western blotting results showed that Kca3.1 mRNA and protein levels were greater in PASMC after hypoxia exposure for 24 hours. Elevated BMP2 (bone morphogenetic protein 2) levels and decreased BMPR2/Smad1 signaling activation were also observed under hypoxia, which were significantly attenuated by TRAM-34 intervention. CONCLUSIONS: These results suggest that Kca3.1 inhibition with TRAM-34 inhibited hypoxia-induced PASMC proliferation in the G0/G1 phase. The capability of TRAM-34 to increase BMPR2/p-Smad1 signaling may be part of the mechanisms for hypoxia-induced cell proliferation. Thus, our study implies that blockade of kca3.1 might provide benefits to attenuating PAH vascular remodeling.

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Kcnn4	Rat	cellular response to hypoxia		IEP			RGD
Kcnn4	Rat	positive regulation of G0 to G1 transition		IMP			RGD
Kcnn4	Rat	regulation of smooth muscle cell proliferation		IMP			RGD

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Genes (Rattus norvegicus)

Kcnn4 (potassium calcium-activated channel subfamily N member 4)

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