Purinergic P2Y2 Receptor-Induced Activation of Endothelial TRPV4 Channels Mediates Lung Ischemia-Reperfusion Injury.

Autor:	Kuppusamy M; Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908., Ta HQ; Department of Surgery, University of Virginia, Charlottesville, VA 22908., Davenport HN; Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908., Bazaz A; Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908., Kulshrestha A; Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908., Daneva Z; Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908., Chen YL; Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908., Carrott PW; Department of Surgery, University of Virginia, Charlottesville, VA 22908., Laubach VE; Department of Surgery, University of Virginia, Charlottesville, VA 22908., Sonkusare SK; Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908.; Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 May 31. Date of Electronic Publication: 2023 May 31.
DOI:	10.1101/2023.05.29.542520
Abstrakt:	Lung ischemia-reperfusion injury (IRI), characterized by inflammation, vascular permeability, and lung edema, is the major cause of primary graft dysfunction after lung transplantation. We recently reported that endothelial cell (EC) TRPV4 channels play a central role in lung edema and dysfunction after IR. However, the cellular mechanisms for lung IR-induced activation of endothelial TRPV4 channels are unknown. In a left-lung hilar ligation model of IRI in mice, we found that lung IR increases the efflux of extracellular ATP (eATP) through pannexin 1 (Panx1) channels at the EC membrane. Elevated eATP activated elementary Ca 2+ influx signals through endothelial TRPV4 channels through purinergic P2Y2 receptor (P2Y2R) signaling. P2Y2R-dependent activation of TRPV4 channels was also observed in human and mouse pulmonary microvascular endothelium in ex vivo and in vitro surrogate models of lung IR. Endothelium-specific deletion of P2Y2R, TRPV4, and Panx1 in mice had substantial protective effects against lung IR-induced activation of endothelial TRPV4 channels, lung edema, inflammation, and dysfunction. These results identify endothelial P2Y2R as a novel mediator of lung edema, inflammation, and dysfunction after IR, and show that disruption of endothelial Panx1-P2Y2R-TRPV4 signaling pathway could represent a promising therapeutic strategy for preventing lung IRI after transplantation. Competing Interests: Competing Interests. None.
Databáze:	MEDLINE
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