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RGC-32 (Response Gene to Complement 32) Deficiency Protects Endothelial Cells From Inflammation and Attenuates Atherosclerosis.

ABSTRACT: OBJECTIVE:The objective of this study is to determine the role and underlying mechanisms of RGC-32 (response gene to complement 32 protein) in atherogenesis. APPROACH AND RESULTS: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-? (tumor necrosis factor-?)-induced monocyte-endothelial cell interaction. Mechanistically, RGC-32 mediated the ICAM-1 and VCAM-1 expression, at least partially, through NF (nuclear factor)-?B signaling pathway. RGC-32 directly interacted with NF-?B and facilitated its nuclear translocation and enhanced TNF-?-induced NF-?B binding to ICAM-1 and VCAM-1 promoters. CONCLUSIONS: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-?B signaling pathway.

SUBMITTER: Cui XB

PROVIDER: S-EPMC5864544 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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RGC-32 (Response Gene to Complement 32) Deficiency Protects Endothelial Cells From Inflammation and Attenuates Atherosclerosis.

Cui Xiao-Bing XB Luan Jun-Na JN Dong Kun K Chen Sisi S Wang Yongyi Y Watford Wendy T WT Chen Shi-You SY

Arteriosclerosis, thrombosis, and vascular biology 20180215 4

<h4>Objective</h4>The objective of this study is to determine the role and underlying mechanisms of RGC-32 (response gene to complement 32 protein) in atherogenesis.<h4>Approach and results</h4>RGC-32 was mainly expressed in endothelial cells of atherosclerotic lesions in both ApoE<sup>-/-</sup> (apolipoprotein E deficient) mice and human patients. <i>Rgc</i>-32 deficiency (<i>Rgc32</i><sup>-/-</sup>) attenuated the high-fat diet-induced and spontaneously developed atherosclerotic lesions in Apo ...[more]

PMID: 29449334

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Project description:Objective- Inflammatory stimuli enhance the progression of atherosclerotic disease. Inflammation also increases the expression of hepcidin, a hormonal regulator of iron homeostasis, which decreases intestinal iron absorption, reduces serum iron levels and traps iron within macrophages. The role of macrophage iron in the development of atherosclerosis remains incompletely understood. The objective of this study was to investigate the effects of hepcidin deficiency and decreased macrophage iron on the development of atherosclerosis. Approach and Results- Hepcidin- and LDL (low-density lipoprotein) receptor-deficient ( Hamp-/-/ Ldlr-/-) mice and Hamp+/+/ Ldlr-/- control mice were fed a high-fat diet for 21 weeks. Compared with control mice, Hamp-/-/ Ldlr-/- mice had decreased aortic macrophage activity and atherosclerosis. Because hepcidin deficiency is associated with both increased serum iron and decreased macrophage iron, the possibility that increased serum iron was responsible for decreased atherosclerosis in Hamp-/-/ Ldlr-/- mice was considered. Hamp+/+/ Ldlr-/- mice were treated with iron dextran so as to produce a 2-fold increase in serum iron. Increased serum iron did not decrease atherosclerosis in Hamp+/+/ Ldlr-/- mice. Aortic macrophages from Hamp-/-/ Ldlr-/- mice had less labile free iron and exhibited a reduced proinflammatory (M1) phenotype compared with macrophages from Hamp+/+/ Ldlr-/- mice. THP1 human macrophages treated with an iron chelator were used to model hepcidin deficiency in vitro. Treatment with an iron chelator reduced LPS (lipopolysaccharide)-induced M1 phenotypic expression and decreased uptake of oxidized LDL. Conclusions- In summary, in a hyperlipidemic mouse model, hepcidin deficiency was associated with decreased macrophage iron, a reduced aortic macrophage inflammatory phenotype and protection from atherosclerosis. The results indicate that decreasing hepcidin activity, with the resulting decrease in macrophage iron, may prove to be a novel strategy for the treatment of atherosclerosis.

Dataset Information

RGC-32 (Response Gene to Complement 32) Deficiency Protects Endothelial Cells From Inflammation and Attenuates Atherosclerosis.

Publications

RGC-32 (Response Gene to Complement 32) Deficiency Protects Endothelial Cells From Inflammation and Attenuates Atherosclerosis.

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