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

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

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Plasmin-mediated fibrinolysis at the surface of vascular endothelial cells (SVEC) plays a key role in maintaining vascular hemostasis, in which the cAMP pathway participates. After externalization to the SVEC, annexin A2 (ANXA2) serves as a platform for conversion of plasminogen to plasmin. Here we describe a regulatory role of the exchange protein directly activated by cAMP (EPAC) in ANXA2 externalization and vascular fibrinolysis. Knockout of EPAC1 in mice results in a decreased ANXA2 expression on the SVEC associated with increased fibrin deposition and fibrinolytic dysfunction. Reduced levels of EPAC1 are also found in endocardial tissues beneath atrial mural thrombi in patients. Notably, administration of recombinant ANXA2 ameliorates fibrinolytic dysfunction in the EPAC1-null mice. Mechanistically, EPAC1 regulates the SVEC plasminogen conversion depended on ANXA2. EPAC1 promotes tyrosine-23 phosphorylation of ANXA2, a prerequisite for its recruitment to the SVEC. Our data thus reveal a novel regulatory role for EPAC1 in vascular fibrinolysis.

Original languageEnglish (US)
Pages (from-to)1-12
Number of pages12
JournalLife Sciences
Volume221
DOIs
StatePublished - Mar 15 2019

Keywords

  • Annexin A2
  • Atomic force microscopy
  • EPAC1
  • Thrombosis
  • Vascular endothelial fibrinolysis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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  • Cite this

    He, X., Drelich, A., Yu, S., Chang, Q., Gong, D., Zhou, Y., Qu, Y., Yuan, Y., Su, Z., Qiu, Y., Tang, S-J., Gaitas, A., Ksiazek, T., Xu, Z., Zhou, J., Feng, Z., Wakamiya, M., Lu, F., & Gong, B. (2019). Exchange protein directly activated by cAMP plays a critical role in regulation of vascular fibrinolysis. Life Sciences, 221, 1-12. https://doi.org/10.1016/j.lfs.2019.02.014