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SHR Neuro Cancer Cardio Lipid Metab Microb

Csáki, R; Nagaraj, C; Almássy, J; Khozeimeh, MA; Jeremic, D; Olschewski, H; Dobolyi, A; Hoetzenecker, K; Olschewski, A; Enyedi, P; Lengyel, M.
The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension.
Br J Pharmacol. 2024; Doi: 10.1111/bph.16426
Web of Science PubMed FullText FullText_MUG

 

Leading authors Med Uni Graz

Olschewski Andrea

Co-authors Med Uni Graz

Chandran Nagaraj

JEREMIC Dusan

Olschewski Horst

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Abstract:

BACKGROUND AND PURPOSE: Pulmonary arterial hypertension (PAH) is a progressive disease in which chronic membrane potential (E_m) depolarisation of the pulmonary arterial smooth muscle cells (PASMCs) causes calcium overload, a key pathological alteration. Under resting conditions, the negative E_m is mainly set by two pore domain potassium (K_2P) channels, of which the TASK-1 has been extensively investigated. EXPERIMENTAL APPROACH: Ion channel currents and membrane potential of primary cultured human(h) PASMCs were measured using the voltage- and current clamp methods. Intracellular [Ca²⁺] was monitored using fluorescent microscopy. Pulmonary BP and vascular tone measurements were also performed ex vivo using a rat PAH model. KEY RESULTS: TREK-1 was the most abundantly expressed K_2P in hPASMCs of healthy donors and idiopathic(I) PAH patients. Background K⁺-current was similar in hPASMCs for both groups and significantly enhanced by the TREK activator ML-335. In donor hPASMCs, siRNA silencing or pharmacological inhibition of TREK-1 caused depolarisation, reminiscent of the electrophysiological phenotype of idiopathic PAH. ML-335 hyperpolarised donor hPASMCs and normalised the E_m of IPAH hPASMCs. A close link was found between TREK-1 activity and intracellular Ca²⁺-signalling using a channel activator, ML-335, and an inhibitor, spadin. In the rat, ML-335 relaxed isolated pre-constricted pulmonary arteries and significantly decreased pulmonary arterial pressure in the isolated perfused lung. CONCLUSIONS AND IMPLICATIONS: These data suggest that TREK-1is a key factor in E_m setting and Ca²⁺ homeostasis of hPASMC, and therefore, essential for maintenance of a low resting pulmonary vascular tone. Thus TREK-1 may represent a new therapeutic target for PAH.

Find related publications in this database (Keywords)

ML-335

pulmonary arterial hypertension (PAH)

pulmonary arterial smooth muscle cells (PASMC)

spadin

TREK-1

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