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

• Published in: Life sciences (1973) Vol. 221; pp. 1 - 12
• Main Authors: He, Xi, Drelich, Aleksandra, Yu, Shangyi, Chang, Qing, Gong, Dejun, Zhou, Yixuan, Qu, Yue, Yuan, Yang, Su, Zhengchen, Qiu, Yuan, Tang, Shao-Jun, Gaitas, Angelo, Ksiazek, Thomas, Xu, Zhiyun, Zhou, Jia, Feng, Zongdi, Wakamiya, Maki, Lu, Fanglin, Gong, Bin
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 15.03.2019; Elsevier BV
• Subjects: Animals; Annexin A2; Annexin A2 - metabolism; Atomic force microscopy; Cell Membrane; Conversion; Cyclic AMP; Cyclic AMP - metabolism; Endothelial cells; Endothelial Cells - metabolism; Endothelial Cells - physiology; Endothelium, Vascular; EPAC1; Exchanging; Fibrin; Fibrinolysin - metabolism; Fibrinolysis; Fibrinolysis - physiology; Guanine Nucleotide Exchange Factors - genetics; Guanine Nucleotide Exchange Factors - metabolism; Guanine Nucleotide Exchange Factors - physiology; Hemostasis; Hemostatics; Homeostasis; Humans; Mice; Mice, Knockout; Phosphorylation; Plasmin; Plasminogen - metabolism; Proteins; Proteolysis; Thrombosis; Tyrosine; Vascular endothelial fibrinolysis; Atomic force microscopy; Vascular endothelial fibrinolysis; Annexin A2; EPAC1; Thrombosis
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2019.02.014

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.