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SHR Neuro Cancer Cardio Lipid Metab Microb

Skofic Maurer, D; Zabini, D; Nagaraj, C; Sharma, N; Lengyel, M; Nagy, BM; Frank, S; Klepetko, W; Gschwandtner, E; Enyedi, P; Kwapiszewska, G; Olschewski, H; Olschewski, A.
Endothelial Dysfunction Following Enhanced TMEM16A Activity in Human Pulmonary Arteries.
Cells. 2020; 9(9): Doi: 10.3390/cells9091984 [OPEN ACCESS]
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Leading authors Med Uni Graz: Olschewski Andrea
Co-authors Med Uni Graz: Chandran Nagaraj; Frank Sasa; Gschwandtner Elisabeth; Kwapiszewska-Marsh Grazyna; Nagy Miklos Bence; Olschewski Horst; Sharma Neha; Skofic Maurer Davor; Zabini Diana
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Abstract:: Endothelial dysfunction is one of the hallmarks of different vascular diseases, including pulmonary arterial hypertension (PAH). Ion channelome changes have long been connected to vascular remodeling in PAH, yet only recently has the focus shifted towards Ca²⁺-activated Cl^- channels (CaCC). The most prominent member of the CaCC TMEM16A has been shown to contribute to the pathogenesis of idiopathic PAH (IPAH) in pulmonary arterial smooth muscle cells, however its role in the homeostasis of healthy human pulmonary arterial endothelial cells (PAECs) and in the development of endothelial dysfunction remains underrepresented. Here we report enhanced TMEM16A activity in IPAH PAECs by whole-cell patch-clamp recordings. Using adenoviral-mediated TMEM16A increase in healthy primary human PAECs in vitro and in human pulmonary arteries ex vivo, we demonstrate the functional consequences of the augmented TMEM16A activity: alterations of Ca²⁺ dynamics and eNOS activity as well as decreased NO production, PAECs proliferation, wound healing, tube formation and acetylcholine-mediated relaxation of human pulmonary arteries. We propose that the ERK1/2 pathway is specifically affected by elevated TMEM16A activity, leading to these pathological changes. With this work we introduce increased TMEM16A activity in the cell membrane of human PAECs for the development of endothelial dysfunction in PAH.
Find related publications in this database (using NLM MeSH Indexing): Anoctamin-1 -; Endothelial Cells - metabolism; Humans -; Neoplasm Proteins -; Pulmonary Artery - metabolism
Find related publications in this database (Keywords): TMEM16A; Ano1; pulmonary endothelial cells; endothelial dysfunction; pulmonary hypertension; intracellular calcium; angiogenesis; eNOS uncoupling; benzbromarone; metabolic switch