Empagliflozin prevents oxidative stress in human coronary artery endothelial cells via the NHE/PKC/NOX axis.

Autor:	Li X; Amsterdam, University Medical Centers, Location AMC, Department of Anesthesiology, Laboratory of Experimental Intensive Care and Anesthesiology-L.E.I.C.A, Amsterdam Cardiovascular Science (ACS), Meibergdreef 11, 1105 AZ, Amsterdam, the Netherlands., Wang M; Amsterdam, University Medical Centers, Location AMC, Department of Anesthesiology, Laboratory of Experimental Intensive Care and Anesthesiology-L.E.I.C.A, Amsterdam Cardiovascular Science (ACS), Meibergdreef 11, 1105 AZ, Amsterdam, the Netherlands., Kalina JO; Amsterdam, University Medical Centers, Location AMC, Department of Anesthesiology, Laboratory of Experimental Intensive Care and Anesthesiology-L.E.I.C.A, Amsterdam Cardiovascular Science (ACS), Meibergdreef 11, 1105 AZ, Amsterdam, the Netherlands; Department of Anesthesiology and Intensive Care Medicine, Universitätsklinikum Schleswig-Holstein, Campus Kiel, 24105, Kiel, Germany., Preckel B; Amsterdam, University Medical Centers, Location AMC, Department of Anesthesiology, Laboratory of Experimental Intensive Care and Anesthesiology-L.E.I.C.A, Amsterdam Cardiovascular Science (ACS), Meibergdreef 11, 1105 AZ, Amsterdam, the Netherlands., Hollmann MW; Amsterdam, University Medical Centers, Location AMC, Department of Anesthesiology, Laboratory of Experimental Intensive Care and Anesthesiology-L.E.I.C.A, Amsterdam Cardiovascular Science (ACS), Meibergdreef 11, 1105 AZ, Amsterdam, the Netherlands., Albrecht M; Department of Anesthesiology and Intensive Care Medicine, Universitätsklinikum Schleswig-Holstein, Campus Kiel, 24105, Kiel, Germany., Zuurbier CJ; Amsterdam, University Medical Centers, Location AMC, Department of Anesthesiology, Laboratory of Experimental Intensive Care and Anesthesiology-L.E.I.C.A, Amsterdam Cardiovascular Science (ACS), Meibergdreef 11, 1105 AZ, Amsterdam, the Netherlands., Weber NC; Amsterdam, University Medical Centers, Location AMC, Department of Anesthesiology, Laboratory of Experimental Intensive Care and Anesthesiology-L.E.I.C.A, Amsterdam Cardiovascular Science (ACS), Meibergdreef 11, 1105 AZ, Amsterdam, the Netherlands. Electronic address: N.C.Hauck@amsterdamumc.nl.
Jazyk:	angličtina
Zdroj:	Redox biology [Redox Biol] 2024 Feb; Vol. 69, pp. 102979. Date of Electronic Publication: 2023 Dec 02.
DOI:	10.1016/j.redox.2023.102979
Abstrakt:	Background: Empagliflozin (EMPA) ameliorates reactive oxygen species (ROS) generation in human endothelial cells (ECs) exposed to 10 % stretch, but the underlying mechanisms are still unclear. Pathological stretch is supposed to stimulate protein kinase C (PKC) by increasing intracellular calcium (Ca 2+ ), therefore activating nicotinamide adenine dinucleotide phosphate oxidase (NOX) and promoting ROS production in human ECs. We hypothesized that EMPA inhibits stretch-induced NOX activation and ROS generation through preventing PKC activation. Methods: Human coronary artery endothelial cells (HCAECs) were pre-incubated for 2 h before exposure to cyclic stretch (5 % or 10 %) with either vehicle, EMPA or the PKC inhibitor LY-333531 or PKC siRNA. PKC activity, NOX activity and ROS production were detected after 24 h. Furthermore, the Ca 2+ chelator BAPTA-AM, NCX inhibitor ORM-10962 or NCX siRNA, sodium/potassium pump inhibitor ouabain and sodium hydrogen exchanger (NHE) inhibitor cariporide were applied to explore the involvement of the NHE/Na + /NCX/Ca 2+ in the ROS inhibitory capacity of EMPA. Results: Compared to 5 % stretch, 10 % significantly increased PKC activity, which was reduced by EMPA and PKC inhibitor LY-333531. EMPA and LY-333531 showed a similar inhibitory capacity on NOX activity and ROS generation induced by 10 % stretch, which was not augmented by combined treatment with both drugs. PKC-β knockdown inhibits the NOX activation induced by Ca 2+ and 10 % stretch. BAPTA, pharmacologic or genetic NCX inhibition and cariporide reduced Ca 2+ in static HCAECs and prevented the activation of PKC and NOX in 10%-stretched cells. Ouabain increased ROS generation in cells exposed to 5 % stretch. Conclusion: EMPA reduced NOX activity via attenuation of the NHE/Na + /NCX/Ca 2+ /PKC axis, leading to less ROS generation in HCAECs exposed to 10 % stretch. Competing Interests: Declaration of competing interest Authors declare that there are no conflicts of interest. (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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