Abstract
BackgroundAnnexin A2 (ANXA2), a member of the annexin family of cytosolic Ca2+-binding proteins, plays a pivotal role in vascular biology. Small amounts of this protein and S100A10 protein are exposed on the surface of endothelial cells (ECs). They control fibrinolysis by recruiting tissue-type and urokinase-type plasminogen activators from the plasma. Nutritional studies indicate that two major long-chain polyunsaturated fatty acids (PUFAs), i.e., eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), provide benefits for EC functions. The effects of EPA and DHA on the plasminogen/plasmin system have not been characterized.Methodology/Principal FindingsProteomic analysis of a cultured human umbilical vein EC-derived cell line, HUV-EC-C, showed that cell-associated ANXA2 decreased with EPA treatment and increased with DHA. A small fraction of ANXA2 was bound to the cell surface, which was also affected by these PUFAs following the same trends. Cell surface expression was negatively regulated by protein kinase C (PKC) α-mediated Ser-phosphorylation, which was up- and down-regulated by EPA and DHA, respectively. These PUFAs differentially affected a small fraction of caveolae/rafts-associated ANXA2. In addition to chymotrypsin-like activity in the serum, newly activated plasmin cleaved the ANXA2 on the cell surface at distinct sites in the N-terminal sequence. ANXA2 also bound to membranes released in the medium, which was similarly processed by these proteases. Both the PUFAs did not directly affect the release.Conclusion/SignificanceThese results suggest that EPA and DHA reciprocally control cell surface location of ANXA2. Moreover, cleavage of this protein by plasmin likely resulted in autodigestion of the platform for formation of this protease. In conjunction with termination of the proteolysis by rapid inactivation of plasmin by α-2-antiplasmin and other polypeptide inhibitors, this feedback mechanism may emphasize the benefits of these PUFA in regulation of the initiation of fibrinolysis on the surface of ECs.
Highlights
Vascular endothelial cells (ECs) manifest both the progression and recovery phases of vascular lesions
Using 2D-electrophoresis, we found that spots at 36 kDa were distributed differently in extracts from EPAand docosahexaenoic acid (DHA)-treated cells (Fig. 1)
Nutritional and epidemiological studies have shown that eicosapentaenoic acid (EPA) and DHA in fish oil can decrease the risk of cardiovascular diseases [13,19]
Summary
Vascular endothelial cells (ECs) manifest both the progression and recovery phases of vascular lesions. Multiple proteolytic reactions occur on the surfaces of ECs, modulating various aspects of the cellular environment Of these reactions, the plasminogen/plasmin system, which cleaves and activates plasminogen through tissue and urokinase-type plasminogen activators (tPA and uPA, respectively) is primarily important for fibrinolysis and control of inflammation. The plasminogen/plasmin system, which cleaves and activates plasminogen through tissue and urokinase-type plasminogen activators (tPA and uPA, respectively) is primarily important for fibrinolysis and control of inflammation In this system, participation of annexin A2 (ANXA2) is critical [3]. Annexin A2 (ANXA2), a member of the annexin family of cytosolic Ca2+-binding proteins, plays a pivotal role in vascular biology Small amounts of this protein and S100A10 protein are exposed on the surface of endothelial cells (ECs). The effects of EPA and DHA on the plasminogen/plasmin system have not been characterized
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