Abstract
Backgrounds : Endothelial cell-selective adhesion molecule (ESAM) is a new member of the immunoglobulin superfamily, which is expressed in vascular endothelial cells. Although ESAM has been shown to mediate homohilic adhesion between endothelial cells, the interaction of ESAM and hematopoietic cells has not been ingestigated. Also, the role of ESAM in atherosclerosis remains unclear. In this study, we assessed the role of ESAM in monocyte/ macarophage infiltration, and examined effects of ESAM inactivation in the development atherosclerosis using a murine model of atherosclerosis. Methods and Results : ESAM−/− mice were bred with apoE−/− mice to generate the double knockout mice, and the lesion size of aortic sinus was evaluated histologically between ESAM+/+ apoE−/− and ESAM−/− apoE+/+ mice. Plasma lipid profile was not affected by ESAM deficiency. However, the lesion size was markedly attenuated in ESAM−/− apoE−/− mice compared to ESAM+/+apoE−/− mice. The percentage of MOMA-2-stained area in the aortic sinus lesions was significantly smaller in ESAM-/-apoE−/− mice than in ESAM+/+apoE−/− mice, suggesting that ESAM deficiency reduced the macrophage infiltration in the atheroma. To clarify the mechanism for the reduced macrophage content in the plaque, in vitro adhesion- and transendothelial migration assays were performed between cultured endothelial monolayers and monocyte/macrophage cell line THP-1 cells utilizing siRNA-mediated knockdown of ESAM. These assays revealed that ESAM deficiency in endothelial cells resulted in decreases in monocyte adhesion to the endothelial cells as well as transendothelialmigration. THP-1 cells did not express ESAM, but directly bound to the recommbinant ESAM protein-coated culture plates. Conclusion : ESAM modulates macrophage infiltration into the atheroma through interaction with unidentified ligand(s) on monocytes. ESAM inactivation can reduce susceptibility to atherosclerosis.
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