Atheroprotective Effects of Tumor Necrosis Factor-Stimulated Gene-6.
JACC Basic Transl Sci
; 1(6): 494-509, 2016 Oct.
Article
em En
| MEDLINE
| ID: mdl-30167534
ABSTRACT
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-CoAcholesterol 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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01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
JACC Basic Transl Sci
Ano de publicação:
2016
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Article