GPR55 agonist lysophosphatidylinositol and lysophosphatidylcholine inhibit endothelial cell hyperpolarization via GPR-independent suppression of Na+-Ca2+ exchanger and endoplasmic reticulum Ca2+ refilling.
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Bondarenko AI
Circulatory Physiology Department, Bogomoletz Institute of Physiology NAS of Ukraine, Bogomoletz Str.4, 01024 Kiev, Ukraine; Medical University of Graz, Institute of Molecular Biology and Biochemistry, Graz 8010, Austria. Electronic address: abond01@biph.kiev.ua.
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Montecucco F
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy; IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Largo Benzi 10, 16132 Genoa, Italy.
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Panasiuk O
Circulatory Physiology Department, Bogomoletz Institute of Physiology NAS of Ukraine, Bogomoletz Str.4, 01024 Kiev, Ukraine.
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Sagach V
Circulatory Physiology Department, Bogomoletz Institute of Physiology NAS of Ukraine, Bogomoletz Str.4, 01024 Kiev, Ukraine.
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Sidoryak N
Department of Physiology of Human and Animals, Melitopol State Pedagogical University, Ukraine.
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Brandt KJ
Division of Cardiology, Foundation for Medical Researches, Department of Internal Medicine, University of Geneva, Av. de la Roseraie 64, CH-1211 Geneva 4, Switzerland.
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Mach F
Division of Cardiology, Foundation for Medical Researches, Department of Internal Medicine, University of Geneva, Av. de la Roseraie 64, CH-1211 Geneva 4, Switzerland.
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Published in:
- Vascular pharmacology. - 2017
English
Lysophosphatidylinositol (LPI) and lysophosphatidylcholine (LPC) are lipid signaling molecules that induce endothelium-dependent vasodilation. In addition, LPC suppresses acetylcholine (Ach)-induced responses. We aimed to determine the influence of LPC and LPI on hyperpolarizing responses in vitro and in situ endothelial cells (EC) and identify the underlying mechanisms. Using patch-clamp method, we show that LPI and LPC inhibit EC hyperpolarization to histamine and suppress Na+/Ca2+ exchanged (NCX) currents in a concentration-dependent manner. The inhibition is non-mode-specific and unaffected by intracellular GDPβS infusion and tempol, a superoxide dismutase mimetic. In excised mouse aorta, LPI strongly inhibits the sustained and the peak endothelial hyperpolarization induced by Ach, but not by SKA-31, an opener of Ca2+-dependent K+ channels of intermediate and small conductance. The hyperpolarizing responses to consecutive histamine applications are strongly reduced by NCX inhibition. In a Ca2+-re-addition protocol, bepridil, a NCX inhibitor, and KB-R7943, a blocker of reversed NCX, inhibit the hyperpolarizing responses to Ca2+-re-addition following Ca2+ stores depletion. These finding indicate that LPC and LPI inhibit endothelial hyperpolarization to Ach and histamine independently of G-protein coupled receptors and superoxide anions. Reversed NCX is critical for ER Ca2+ refilling in EC. The inhibition of NCX by LPI and LPC underlies diminished endothelium-dependent responses and endothelial dysfunction accompanied by increased levels of these lipids in the blood.
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bronze
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https://sonar.ch/global/documents/116528
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