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The objective of this study is to determine the role and underlying mechanisms of RGC-32 (response gene to complement 32 protein) in atherogenesis.RGC-32 was mainly expressed in endothelial cells of atherosclerotic lesions in both ApoE−/− (apolipoprotein E deficient) mice and human patients. Rgc-32 deficiency (Rgc32−/−) attenuated the high-fat diet–induced and spontaneously developed atherosclerotic lesions in ApoE−/− mice without affecting serum cholesterol concentration. Rgc32−/− seemed to decrease the macrophage content without altering collagen and smooth muscle contents or lesional macrophage proliferation in the lesions. Transplantation of WT (wild type) mouse bone marrow to lethally irradiated Rgc32−/− mice did not alter Rgc32−/−-caused reduction of lesion formation and macrophage accumulation, suggesting that RGC-32 in resident vascular cells, but not the macrophages, plays a critical role in the atherogenesis. Of importance, Rgc32−/− decreased the expression of ICAM-1 (intercellular adhesion molecule-1) and VCAM-1 (vascular cell adhesion molecule-1) in endothelial cells both in vivo and in vitro, resulting in a decrease in TNF-α (tumor necrosis factor-α)–induced monocyte–endothelial cell interaction. Mechanistically, RGC-32 mediated the ICAM-1 and VCAM-1 expression, at least partially, through NF (nuclear factor)-κB signaling pathway. RGC-32 directly interacted with NF-κB and facilitated its nuclear translocation and enhanced TNF-α–induced NF-κB binding to ICAM-1 and VCAM-1 promoters.RGC-32 mediates atherogenesis by facilitating monocyte–endothelial cell interaction via the induction of endothelial ICAM-1 and VCAM-1 expression, at least partially, through NF-κB signaling pathway.