Background And Purpose: Acurhagin, a member of versatile metalloproteinase disintegrins from Agkistrodon acutus venom, has been identified as a platelet aggregation inhibitor, previously. Here, acurhagin-C, the C-terminal Glu-Cys-Asp (ECD)-containing fragment of acurhagin, was evaluated for its biological activities and potential applications in anti-angiogenic therapy.
Experimental Approach: Human umbilical vein endothelial cells (HUVECs) were treated with acurhagin-C to assay effects on viability, apoptosis, adhesion, migration, invasion, proliferation and angiogenesis. The recognition site and signalling involved for the interactions of acurhagin-C with HUVEC were determined using flow cytometric, electrophoresis and immunoblotting analyses.
Key Results: Acurhagin-C decreased viability and induced apoptosis in HUVEC. It also dose-dependently inhibited HUVEC adhesion to immobilized extracellular matrices fibronectin, collagen I and vitronectin with respective IC(50) values of approximately 0.6, 0.3 and 0.1 microM. Acurhagin-C prevented migration and invasion of HUVEC through vitronectin- and Matrigel-coated barriers respectively. Furthermore, acurhagin-C attenuated fibroblast growth factor-2-primed angiogenesis both in vitro and in vivo, and specifically blocked the binding of anti-alphavbeta3 monoclonal antibody 23C6 to HUVEC in an ECD-dependent manner. However, purified alphavbeta3 also dose-dependently bound to immobilized acurhagin and acurhagin-C with a saturable pattern. Interference with integrin alphavbeta3-mediated functions and promotion of caspase-3 activation by acurhagin-C affected morphology of HUVEC and induced apoptosis.
Conclusions And Implications: Acurhagin-C elicited endothelial anoikis via disruption of alphavbeta3/focal adhesion kinase/phosphatidylinositol 3-kinase/Akt survival cascade and subsequent initiation of the procaspase-3 apoptotic signalling pathway.
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| http://dx.doi.org/10.1111/j.1476-5381.2010.00781.x | DOI Listing |
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