Abstract 211: Response Gene to Complement 32 Deficiency Protects Endothelial Cell From Inflammation and Attenuates Atheroslcerosis

Abstract

Response gene to complement 32 (RGC-32) is involved in diet-induced obesity and hepatic steatosis. Therefore, we hypothesized that RGC-32 plays a role in atherosclerosis. Our current study showed that RGC-32 expression was dramatically induced in endothelial cells (ECs) of the atherosclerotic lesions from both apolipoprotein E-deficient (ApoE -/- ) mice and diseased human arteries. RGC-32 deficiency (Rgc32 -/- ) significantly attenuated the high-fat diet-induced and spontaneously developed atherogenesis in ApoE -/- mice without affecting the serum lipid profiles. In addition, Rgc32 -/- decreased the macrophage content without affecting fibrous cap size. Rgc32 -/- in bone marrow cells had no effect on atherosclerosis development, and Rgc32 -/- mice transplanted with wild-type (WT) bone marrow cells exhibited decreased atherosclerotic lesion area and macrophage infiltration, suggesting that RGC-32 in resident vascular cells plays a critical role in the atherogenesis. Rgc32 -/- decreased the expression of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in ECs both in vivo and in vitro , resulting in a decreased monocyte-EC interaction. Mechanistically, RGC-32 regulated ICAM-1 and VCAM-1 transcription via activation of nuclear factor (NF)-κB. It appeared that RGC-32 interacted with NF-κB, which facilitated NF-κB binding to ICAM-1 and VCAM-1 promoters. Indeed, blockade of NF-κB activity by its selective inhibitor ammonium pyrrolidinedithiocarbamate blocked RGC-32-induced ICAM-1 and VCAM-1 expression. In conclusion, RGC-32 promoted atherogenesis by inducing monocyte-EC interaction through NF-κB-dependent induction of endothelial ICAM-1 and VCAM-1 expression.