Abstract 9418: Preventive Effects of Tumor Necrosis Factor-Stimulated Gene-6 on Atherosclerosis
Introduction: Atherosclerosis is the complex lesion that consists of endothelial inflammation, macrophage foam cell formation, vascular smooth muscle cell (VSMC) proliferation, and extracellular matrix production. Tumor necrosis factor-stimulated gene-6 (TSG-6), an anti-inflammatory protein, was shown to be localized in the artery injury-induced rat neointima. However, the modulatory effect of TSG-6 on atherogenesis has not been reported.
Objective and Methods: This study was performed to evaluate the atheroprotective effects of TSG-6 on human endothelial cells (ECs), human monocyte-derived macrophages, human aortic smooth muscle cells (HASMCs), and aortic lesions in apolipoprotein E-deficient (ApoE-/-) mice.
Results: TSG-6 was expressed at higher levels in human ECs than monocytes, macrophages, and HASMCs. TSG-6 significantly suppressed oxidized low-density lipoprotein-induced foam cell formation associated with reduced expression levels of CD36 and acyl-CoA:cholesterol acyltransferase-1 (ACAT1) in human macrophages. TSG-6 significantly suppressed the proliferation of human ECs and HASMCs, but increased the expressions of clloagen-1 and metalloproteinase-2 in HASMCs. Four-week-infusion of TSG-6 into ApoE-/- mice significantly retarded the development of aortic atherosclerotic lesions with reduced monocyte/macrophage and VSMC contents. Inactivation of inflammasome, such as apoptosis-associated speck-like protein containing a caspase recruitment domain, C-reactive protein, and nuclear factor-κB, was observed in exudate peritoneal macrophages from ApoE-/- mice infused with TSG-6 compared to those infused with saline (control).
Conclusions: These results indicate that TSG-6 prevents atherogenesis by suppressing the inflammatory responses, foam cell formation associated with CD36 and ACAT1 down-regulation in macrophages, and VSMC proliferation. Thus TSG-6 based treatments, e.g. this peptide itself and/or its analogues, are expected to emerge as a new line of therapy against atherosclerosis and its related diseases.
Author Disclosures: R. Watanabe: None. K. Watanabe: None. R. Shirai: None. H. Konii: None. K. Sato: None. T. Watanabe: None.
- © 2014 by American Heart Association, Inc.