Protective Role of Smad6 in Inflammation-Induced Valvular Cell Calcification.
Protective Role of Smad6 in Inflammation-Induced Valvular Cell Calcification.
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DOI：
10.1002/jcb.25186
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发表时间：
2015-10
影响因子：
4
通讯作者：
Tintut, Yin
中科院分区：
文献类型：
--
作者：
Li, Xin;Lim, Jina;Lu, Jinxiu;Pedego, Taylor M.;Demer, Linda;Tintut, Yin
钙化性主动脉血管和瓣膜病（CAVD）与高脂血症相关，其影响通过慢性炎症发生。有证据表明，抑制性小母亲对decapentaplegic（I-Smads; Smad 6和7）调节瓣膜胚胎发生，并可能作为一个缓解因素CAVD。然而，I-Smads是否调节炎症诱导的钙化性血管病变尚不清楚。因此，我们研究了I-Smads在动脉粥样硬化钙化中的作用。结果显示，与正常脂血症小鼠相比，高脂血症小鼠主动脉和瓣膜组织中Smad 6的表达降低，而Smad 7的表达没有降低，而肿瘤坏死因子α（TNF-α）的表达上调。为了测试这种效应是否是对炎性细胞因子的反应，我们从血脂正常的小鼠中分离出小鼠主动脉瓣小叶和培养的瓣膜间质细胞（mVIC）。通过免疫化学，mVIC波形蛋白呈强阳性，平滑肌α肌动蛋白呈弱阳性，内皮细胞标志物呈阴性。TNF-α上调mVIC中的碱性磷酸酶（ALP）活性和基质矿化。通过基因表达分析，TNF-α显著上调骨形态发生蛋白2（BMP-2）的表达，同时下调Smad 6的表达。Smad 7的表达没有受到显著影响。为了进一步测试Smad 6对TNF-α诱导的瓣膜细胞钙化的作用，我们使用慢病毒转染敲低Smad 6表达。在转染Smad 6 shRNA的细胞中，与对照细胞相比，TNF-α进一步增强了ALP活性、BMP-2、Wnt和氧化还原调节基因的表达以及基质矿化。这些发现表明TNF-α诱导瓣膜和血管细胞钙化，部分是通过特异性降低BMP-2信号传导抑制剂Smad 6的表达。
Calcific aortic vascular and valvular disease (CAVD) is associated with hyperlipidemia, the effects of which occur through chronic inflammation. Evidence suggests that inhibitory small mothers against decapentaplegic (I-Smads; Smad6 and 7) regulate valve embryogenesis and may serve as a mitigating factor in CAVD. However, whether I-Smads regulate inflammation-induced calcific vasculopathy is not clear. Therefore, we investigated the role of I-Smads in atherosclerotic calcification. Results showed that expression of Smad6, but not Smad7, was reduced in aortic and valve tissues of hyperlipidemic compared with normolipemic mice, while expression of tumor necrosis factor alpha (TNF-a) was upregulated. To test whether the effects are in response to inflammatory cytokines, we isolated murine aortic valve leaflets and cultured valvular interstitial cells (mVIC) from the normolipemic mice. By immunochemistry, mVICs were strongly positive for vimentin, weakly positive for smooth muscle alpha actin, and negative for an endothelial cell marker. TNF-a upregulated alkaline phosphatase (ALP) activity and matrix mineralization in mVICs. By gene expression analysis, TNF-a significantly upregulated bone morphogenetic protein 2 (BMP-2) expression while downregulating Smad6 expression. Smad7 expression was not significantly affected. To further test the role of Smad6 on TNF-a-induced valvular cell calcification, we knocked down Smad6 expression using lentiviral transfection. In cells transfected with Smad6 shRNA, TNF-a further augmented ALP activity, expression of BMP-2, Wnt- and redox-regulated genes, and matrix mineralization compared with the control cells. These findings suggest that TNF-a induces valvular and vascular cell calcification, in part, by specifically reducing the expression of a BMP-2 signaling inhibitor, Smad6.
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影响因子：
8.7
作者：
Dhore, CR;Cleutjens, JPM;Daemen, MJAP
通讯作者：
Daemen, MJAP
影响因子：
4.8
作者：
Lai, Chung-Fang;Shao, Jian-Su;Towler, Dwight A.
通讯作者：
Towler, Dwight A.
DOI：
10.1161/atvbaha.107.153668
发表时间：
2007-12-01
影响因子：
8.7
作者：
Al-Aly, Ziyad;Shao, Jian-Su;Towler, Dwight A.
通讯作者：
Towler, Dwight A.
影响因子：
4.6
作者：
Bruunsgaard, H;Skinhoj, P;Pedersen, BK
通讯作者：
Pedersen, BK
磷酸盐和焦磷酸盐介导PKA诱导的血管细胞钙化。
DOI：
10.1016/j.bbrc.2008.07.062
发表时间：
2008-09-26
影响因子：
3.1
作者：
Huang, Michael S.;Sage, Andrew P.;Lu, Jinxiu;Demer, Linda L.;Tintut, Yin
通讯作者：
Tintut, Yin