Author:
Xiao Jie,Zhang Ben,Su Zhengchen,Liu Yakun,Shelite Thomas R.,Chang Qing,Wang Pingyuan,Bukreyev Alexander,Soong Lynn,Jin Yang,Ksiazek Thomas,Gaitas Angelo,Rossi Shannan L.,Zhou Jia,Laposata Michael,Saito Tais B.,Gong Bin
Abstract
AbstractCoagulopathy is associated with both inflammation and infection, including infection with the novel SARS-CoV-2 (COVID-19). Endothelial cells (ECs) fine tune hemostasis via cAMP-mediated secretion of von Willebrand factor (vWF), which promote the process of clot formation. Theexchangeprotein directlyactivated bycAMP (EPAC) is a ubiquitously expressed intracellular cAMP receptor that plays a key role in stabilizing ECs and suppressing inflammation. To assess whether EPAC could regulate vWF release during inflammation, we utilized ourEPAC1-null mouse model and revealed an increased secretion of vWF in endotoxemic mice in the absence of the EPAC1 gene. Pharmacological inhibition of EPAC1in vitromimicked theEPAC1−/− phenotype. EPAC1 regulated TNFα-triggered vWF secretion from human umbilical vein endothelial cells (HUVECs) in a phosphoinositide 3-kinases (PI3K)/endothelial nitric oxide synthase (eNOS)-dependent manner. Furthermore, EPAC1 activation reduced inflammation-triggered vWF release, bothin vivoandin vitro. Our data delineate a novel regulatory role of EPAC1 in vWF secretion and shed light on potential development of new strategies to controlling thrombosis during inflammation.Key PointPI3K/eNOS pathway-mediated, inflammation-triggered vWF secretion is the target of the pharmacological manipulation of the cAMP-EPAC system.
Publisher
Cold Spring Harbor Laboratory
Cited by
3 articles.
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