期刊
HYPERTENSION
卷 66, 期 4, 页码 757-766出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/HYPERTENSIONAHA.115.06004
关键词
angiotensin II; cardiac fibrosis; hypertension; remodeling; tenascin-C
资金
- Ministry of Education, Culture Sports, Science and Technology of Japan [19590813, 21590927]
- Ministry of Health, Labour and Welfare of Japan
- New Investigator Travel Award
- Grants-in-Aid for Scientific Research [21590927, 19590813] Funding Source: KAKEN
Tenascin-C (TN-C) is an extracellular matrix protein not detected in normal adult heart, but expressed in several heart diseases closely associated with inflammation. Accumulating data suggest that TN-C may play a significant role in progression of ventricular remodeling. In this study, we aimed to elucidate the role of TN-C in hypertensive cardiac fibrosis and underlying molecular mechanisms. Angiotensin II was administered to wild-type and TN-C knockout mice for 4 weeks. In wild-type mice, the treatment induced increase of collagen fibers and accumulation of macrophages in perivascular areas associated with deposition of TN-C and upregulated the expression levels of interleukin-6 and monocyte chemoattractant protein-1 as compared with wild-type/control mice. These changes were significantly reduced in TN-C knockout/angiotensin II mice. In vitro, TN-C accelerated macrophage migration and induced accumulation of integrin V3 in focal adhesions, with phosphorylation of focal adhesion kinase (FAK) and Src. TN-C treatment also induced nuclear translocation of phospho-NF-B and upregulated interleukin-6 expression of macrophages in an NF-B-dependent manner; this being suppressed by inhibitors for integrin V3 and Src. Furthermore, interleukin-6 upregulated expression of collagen I by cardiac fibroblasts. TN-C may enhance inflammatory responses by accelerating macrophage migration and synthesis of proinflammatory/profibrotic cytokines via integrin V3/FAK-Src/NF-B, resulting in increased fibrosis.
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