Exchange protein directly activated by cAMP plays a critical role in regulation of vascular fibrinolysis

Xi He, Aleksandra Drelich, Qing Chang, Dejun Gong, Yixuan Zhou, Yue Qu, Shangyi Yu, Yang Yuan, Jiao Qian, Yuan Qiu, Shao Jun Tang, Angelo Gaitas, Thomas Ksiazek, Zhiyun Xu, Maki Wakamiya, Fanglin Lu, Bin Gong

Research output: Contribution to journalArticlepeer-review

Abstract

Rationale To maintain vascular patency, endothelial cells (ECs) actively regulate hemostasis. Among the myriad of pathways by which they control both fibrin formation and fibrinolysis is EC expression of annexin A2 (ANXA2) in a heterotetrameric complex with S100A10 [(ANXA2-S100A10)2]. This complex is a well-recognized endothelial surface platform for the activation of plasminogen by tissue plasminogen activator. A noteworthy advance in this field came about when it was shown that the cAMP pathway is linked to the regulation of (ANXA2-S100A10)2 in ECs. Objective These findings prompted us to determine whether a druggable target, namely the exchange protein directly activated by cAMP (EPAC) pathway, plays a role in vascular luminal fibrinolysis. Methods and Results Taking advantage of our Epac1-null mouse model, we found that depletion of Epac1 results in fibrin deposition, fibrinolytic dysfunction, and decreased endothelial surface ANXA2 in mice, which are similar to phenomena discovered in ANXA2-null and S100A10-null mice. We observed upregulation of EPAC1 and downregulation of fibrin in endocardial tissues beneath atrial mural thrombi in humans. Of note, our thrombosis model revealed that dysfunction of fibrinolysis in EPAC1-null mice can be ameliorated by recombinant ANXA2. Furthermore, we demonstrated that suppression of EPAC1 using a small-molecule inhibitor (ESI09) reduces the expression of ANXA2 in lipid rafts and impedes ANXA2 association with S100A10. Endothelial apical surface expression of both ANXA2 and S100A10 were markedly decreased in ESI09-treated ECs, which was corroborated by results from a nanoforce spectroscopy study. Moreover, inactivation of EPAC1 decreases tyrosine 23 phosphorylation of ANXA2 in the cell membrane compartment. Conclusions Our data reveal a novel role for EPAC1 in vascular fibrinolysis, by showing that EPAC1 is responsible for the translocation of ANXA2 to the EC surface. This process promotes conversion of plasminogen to plasmin, thereby enhancing local fibrinolytic activity.

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StatePublished - Oct 1 2017

Keywords

  • annexin A2
  • atomic force microscopy
  • EPAC1
  • thrombosis
  • vascular endothelial fibrinolysis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Fingerprint Dive into the research topics of 'Exchange protein directly activated by cAMP plays a critical role in regulation of vascular fibrinolysis'. Together they form a unique fingerprint.

Cite this