Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw 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
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- Führende Autor*innen der Med Uni Graz
- Olschewski Andrea
- Co-Autor*innen der 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 (Em) depolarisation of the pulmonary arterial smooth muscle cells (PASMCs) causes calcium overload, a key pathological alteration. Under resting conditions, the negative Em is mainly set by two pore domain potassium (K2P) 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 K2P 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 Em 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 Em 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