| First Author | Nosaka M | Year | 2018 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 38 |
| Issue | 11 | Pages | 2638-2650 |
| PubMed ID | 30354252 | Mgi Jnum | J:285145 |
| Mgi Id | MGI:6385457 | Doi | 10.1161/ATVBAHA.118.311194 |
| Citation | Nosaka M, et al. (2018) Contribution of the TNF-alpha (Tumor Necrosis Factor-alpha)-TNF-Rp55 (Tumor Necrosis Factor Receptor p55) Axis in the Resolution of Venous Thrombus. Arterioscler Thromb Vasc Biol 38(11):2638-2650 |
| abstractText | Objective- Deep vein thrombosis results from a combination of risk factors including genetic conditions, obesity, drugs, pregnancy, aging, and malignancy. We examined pathophysiological roles of the TNF-alpha (tumor necrosis factor-alpha)-TNF-Rp55 (tumor necrosis factor receptor p55) axis in thrombus resolution using Tnfrp55(-/-) (TNF-Rp55-deficient) mice. Approach and Results- On ligating the inferior vena cava of wild-type (WT) mice, venous thrombi formed and grew progressively until 5 days but shrunk to <50% of the thrombus weight at day 14. Concomitantly, inferior vena cava ligation enhanced intrathrombotic gene expression of Tnfa and Tnfrp55, and intrathrombotic macrophages expressed both TNF-alpha and TNF-Rp55 proteins. In Tnfrp55(-/-) mice treated with the same manner, thrombus formed at a similar rate for 5 days, but shrinking was delayed compared with WT mice. Moreover, the blood flow recovery in thrombosed inferior vena cava was suspended in Tnfrp55(-/-) mice compared with WT mice. Intrathrombotic Plau (urokinase-type plasminogen activator), Mmp2 (matrix metalloproteinase 2), and Mmp9 (matrix metalloproteinase 9) mRNA expression was significantly reduced in Tnfrp55(-/-) mice, compared with WT ones. Supportingly, the administration of anti-TNF-alpha antibody or TNF-alpha inhibitor (etanercept) delayed the thrombus resolution in WT mice. Furthermore, TNF-alpha treatment enhanced gene expression of Plau, Mmp2, and Mmp9 in WT macrophages but not Tnfrp55(-/-) macrophages. These effects were significantly suppressed by ERK (extracellular signal regulated kinase) and NF-kappaB (nuclear factor-kappa B) inhibitors. Therefore, the lack of TNF-Rp55 has detrimental roles in the thrombus resolution by suppressing PLAU, MMP-2, and MMP-9 expression. In contrast, TNF-alpha administration accelerated thrombus resolution in WT but not Tnfrp55(-/-) mice. Conclusions- The TNF-alpha-TNF-Rp55 axis may have essential roles in the resolution of venous thrombus in mice. |
