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JACC Basic Transl Sci. 2016 Oct 31;1(6):494-509. doi: 10.1016/j.jacbts.2016.07.008. eCollection 2016 Oct.

Atheroprotective Effects of Tumor Necrosis Factor-Stimulated Gene-6.

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Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
Department of Pathology, National Cerebral and Cardiovascular Center, Osaka, Japan.
Showa University Research Institute for Sport and Exercise Sciences, Yokohama, Japan.
Department of Medicine, Showa University School of Medicine, Tokyo, Japan.


Tumor necrosis factor-stimulated gene-6 (TSG-6), an anti-inflammatory protein, was shown to be localized in the neointima of injury-induced rat arteries. However, the modulatory effect of TSG-6 on atherogenesis has not yet been reported. We aimed to evaluate the atheroprotective effects of TSG-6 on human endothelial cells (HECs), human monocyte-derived macrophages (HMDMs), human aortic smooth muscle cells (HASMCs) in vitro, and aortic lesions in apolipoprotein E-deficient mice, along with expression levels of TSG-6 in coronary lesions and plasma from patients with coronary artery disease (CAD). TSG-6 was abundantly expressed in HECs, HMDMs, and HASMCs in vitro. TSG-6 significantly suppressed cell proliferation and lipopolysaccharide-induced up-regulation of monocyte chemotactic protein-1, intercellular adhesion molecule-1, and vascular adhesion molecule-1 in HECs. TSG-6 significantly suppressed inflammatory M1 phenotype and suppressed oxidized low-density lipoprotein-induced foam cell formation associated with down-regulation of CD36 and acyl-CoA:cholesterol acyltransferase-1 in HMDMs. In HASMCs, TSG-6 significantly suppressed migration and proliferation, but increased collagen-1 and -3 expressions. Four-week infusion of TSG-6 into apolipoprotein E-deficient mice significantly retarded the development of aortic atherosclerotic lesions with decreased vascular inflammation, monocyte/macrophage, and SMC contents and increased collagen fibers. In addition, it decreased peritoneal M1 macrophages with down-regulation of inflammatory molecules and lowered plasma total cholesterol levels. In patients with CAD, plasma TSG-6 levels were significantly increased, and TSG-6 was highly expressed in the fibrous cap within coronary atherosclerotic plaques. These results suggest that TSG-6 contributes to the prevention and stability of atherosclerotic plaques. Thus, TSG-6 may serve as a novel therapeutic target for CAD.


ABCA1, ATP-binding cassette transporter A1; ACAT1, acyl-CoA:cholesterol acyltransferase-1; AngII, angiotensin II; ApoE−/−, apolipoprotein E deficient; CAD, coronary artery disease; ECM, extracellular matrix; HASMC, human aortic smooth muscle cell; HMDM, human monocyte-derived macrophage; HUVEC, human umbilical vein endothelial cell; MMP, matrix metalloproteinase; TIMP, tissue inhibitor of metalloproteinase; TSG, tumor necrosis factor stimulated gene; TSG-6; VSMC, vascular smooth muscle cell; atherosclerosis; coronary artery disease; endothelial cell; macrophage; oxLDL, oxidized low-density lipoprotein; vascular smooth muscle cell

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