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GPR55 agonist lysophosphatidylinositol and lysophosphatidylcholine inhibit endothelial cell hyperpolarization via GPR-independent suppression of Na+-Ca2 + exchanger and endoplasmic reticulum Ca2 + refilling

Bondarenko, Alexander and Montecucco, Fabrizio and Panasiuk, Olga and Sagach, Vadim and Sidoryak, Nataliya and Brandt, Karim and Mach, Francois (2017) GPR55 agonist lysophosphatidylinositol and lysophosphatidylcholine inhibit endothelial cell hyperpolarization via GPR-independent suppression of Na+-Ca2 + exchanger and endoplasmic reticulum Ca2 + refilling. Vascul Pharmacol (89). pp. 39-48.

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Abstract

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 + /Ca 2+ 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 Ca 2+ - dependent K + channels of intermediate and small conductance. The hyperpolarizing responses to consecutive histamine applications are strongly reduced by NCX inhibition. In a Ca 2+ -re-addition protocol, bepridil, a NCX inhibitor, and KB-R7943, a blocker of reversed NCX, inhibit the hyperpolarizing responses to Ca 2+ -re-addition following Ca 2+ 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 Ca 2+ 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.

Item Type: Article
Subjects: Q Наука > QP Фізіологія
Divisions: Хіміко-біологічний факультет > Кафедра анатомії і фізіології людини та тварин
Depositing User: admin admin mdpu
Date Deposited: 06 Jun 2019 07:52
Last Modified: 06 Jun 2019 07:52
URI: http://eprints.mdpu.org.ua/id/eprint/4454

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