The maintenance of endothelial barrier is critical for the vascular homeostasis and is maintained by the interaction of adherens junction (AJ) and tight junction (TJ) proteins between adjacent cells. This interaction is stabilized by actin cytoskeleton forming cortical actin ring. Here, we developed a novel vascular leakage blocker, Sac-1004 and investigated its mechanism of action in endothelial cells (ECs). Sac-1004 inhibited endothelial hyperpermeability induced by vascular endothelial growth factor, histamine and thrombin via stabilization of cortical actin ring and AJ proteins at the cell-cell junction. Treatment of Sac-1004 in ECs increased cAMP levels and activated Rac, both of which are known to strengthen endothelial barrier. Furthermore, Sac-1004 induced phosphorylation of cortactin and its localization at cell membrane that is essential for the stabilization of cortical actin ring. These effects of Sac-1004 on ECs were significantly abrogated by dideoxyadenosine (adenylyl cyclase inhibitor) and NSC23766 (Rac inhibitor). Taken together, our findings indicate that Sac-1004 blocks vascular leakage by enhancing endothelial integrity via the cAMP/Rac/cortactin pathway and imply the potential usefulness of Sac-1004 in the development of therapeutic means for vascular leakage-related diseases.
|Number of pages||8|
|Journal||Biochemical and Biophysical Research Communications|
|Publication status||Published - 2013 Jun 7|
Bibliographical noteFunding Information:
This study was supported by grant from Korea Health 21 R&D Project, Ministry of Health Welfare and Family Affairs, Republic of Korea ( A085136 ), Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by Ministry of Education, Science and Technology ( 2012R1A2A1A01002916 ), Bio & Medical Technology Development Program of the National Research Foundation of Korea (NRF) funded by Ministry of Education, Science and Technology (MEST) ( 2011-0019267 ).
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology