JACC: Basic to Translational Science (Oct 2016)

Atheroprotective Effects of Tumor Necrosis Factor–Stimulated Gene-6

  • Rena Watanabe, MS,
  • Hitomi Watanabe, MS,
  • Yui Takahashi, BS,
  • Miho Kojima, BS,
  • Hanae Konii, BS,
  • Kaho Watanabe, MS,
  • Remina Shirai, MS,
  • Kengo Sato, PhD,
  • Taka-aki Matsuyama, MD, PhD,
  • Hatsue Ishibashi-Ueda, MD, PhD,
  • Yoshitaka Iso, MD, PhD,
  • Shinji Koba, MD, PhD,
  • Youichi Kobayashi, MD, PhD,
  • Tsutomu Hirano, MD, PhD,
  • Takuya Watanabe, MD, PhD

DOI
https://doi.org/10.1016/j.jacbts.2016.07.008
Journal volume & issue
Vol. 1, no. 6
pp. 494 – 509

Abstract

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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.

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