Abstract
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.
Highlights
D (HUVECs) in a manner dependent upon inflammatory effector molecules phosphoinositide 3-kinase (PI3K) and endothelial nitric oxide synthase
Coagulopathy is associated with both fundamental mechanism that endothelial cells (ECs) employ to severe inflammation and infections, regulate coagulation is by secreting von including the novel severe acute respiratory Willebrand factor in elongated syndrome coronavirus-2 (SARS-CoV-2), the secretory organelles known as Weibel-Palade causative agent of COVID-19 [1,2,3,4,5]
Systemic infectious diseases can activate ECs and propagate immune responses and inflammation in blood vessels, increasing the risk of microthrombosis, vWF and P-selectin, but WPBs contain a variety of other molecules involved in inflammation [29] and intercellular communication [30], including angiopoietin2 [25], IL-8 [31], and eotaxin-3 [31], and the intra/extracellular vesicle membrane protein CD63 [30]. vWF can determine the assembly of WPBs, and WPB egress is associated with the secretion of vWF and P-selectin from ECs in response to various stimuli [6,22,32]
Summary
D (HUVECs) in a manner dependent upon inflammatory effector molecules phosphoinositide 3-kinase (PI3K) and endothelial nitric oxide synthase (eNOS). We observed that treatment with recombinant TNFα (rTNFα) (50 ng/ml) increased vWF secretion from EPAC1-KO mouse aortic ECs in vitro (P
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