Intracellular receptor EPAC regulates von Willebrand factor secretion from endothelial cells in a PI3K-/eNOS-dependent manner during inflammation.

Autor:	Xiao J; Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA., Zhang B; Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA., Su Z; Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA., Liu Y; Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA., Shelite TR; Department of Internal Medicine, Infectious Diseases, University of Texas Medical Branch, Galveston, Texas, USA., Chang Q; Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA., Qiu Y; Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA., Bei J; Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA., Wang P; Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas, USA., Bukreyev A; Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA., Soong L; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA., Jin Y; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Boston University Medical Campus, Boston, Massachusetts, USA., Ksiazek T; Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA., Gaitas A; The Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Rossi SL; Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA., Zhou J; Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas, USA., Laposata M; Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA., Saito TB; Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA., Gong B; Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA. Electronic address: bigong@utmb.edu.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2021 Nov; Vol. 297 (5), pp. 101315. Date of Electronic Publication: 2021 Oct 20.
DOI:	10.1016/j.jbc.2021.101315
Abstrakt:	Coagulopathy is associated with both inflammation and infection, including infections with novel severe acute respiratory syndrome coronavirus-2, the causative agent Coagulopathy is associated with both inflammation and infection, including infection with novel severe acute respiratory syndrome coronavirus-2, the causative agent of COVID-19. Clot formation is promoted via cAMP-mediated secretion of von Willebrand factor (vWF), which fine-tunes the process of hemostasis. The exchange protein directly activated by cAMP (EPAC) is a ubiquitously expressed intracellular cAMP receptor that plays a regulatory role in suppressing inflammation. To assess whether EPAC could regulate vWF release during inflammation, we utilized our EPAC1-null mouse model and revealed increased secretion of vWF in endotoxemic mice in the absence of the EPAC1 gene. Pharmacological inhibition of EPAC1 in vitro mimicked the EPAC1-/- phenotype. In addition, EPAC1 regulated tumor necrosis factor-α-triggered vWF secretion from human umbilical vein endothelial cells in a manner dependent upon inflammatory effector molecules PI3K and endothelial nitric oxide synthase. Furthermore, EPAC1 activation reduced inflammation-triggered vWF release, both in vivo and in vitro. Our data delineate a novel regulatory role for EPAC1 in vWF secretion and shed light on the potential development of new strategies to control thrombosis during inflammation. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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