Preferential activation of SMAD1/5/8 on the fibrosa endothelium in calcified human aortic valves--association with low BMP antagonists and SMAD6.
Preferential activation of SMAD1/5/8 on the fibrosa endothelium in calcified human aortic valves--association with low BMP antagonists and SMAD6.
复制标题
钙化人主动脉瓣纤维内皮上 SMAD1/5/8 的优先激活——与低 BMP 拮抗剂和 SMAD6 的关联。
DOI：
10.1371/journal.pone.0020969
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Jo H
中科院分区：
文献类型：
--
作者：
Ankeny RF;Thourani VH;Weiss D;Vega JD;Taylor WR;Nerem RM;Jo H
主动脉瓣(AV)钙化优先发生在纤维侧，而室侧相对不受影响。在这里，我们验证了一个假设，即脑室和纤维内皮细胞中骨形态发生蛋白(BMP)通路的侧向依赖激活与人的房室钙化有关。从房室置换手术中获得的钙化动静脉和心脏移植中未钙化的动静脉动静脉用于免疫组织化学研究。我们发现钙化性纤维组织中Smad1/5/8磷酸化水平高于非钙化性纤维组织，而Smad2/3磷酸化水平(典型的转化生长因子β途径)与非钙化性纤维组织相比差异无统计学意义。有趣的是，我们发现在钙化和非钙化房室尖，BMP-2/4/6在脑室内皮细胞上的表达显著高于纤维组织；然而，BMP拮抗剂(cross vienless-2/BMPER和noggin)在这两种疾病状态下，脑室内皮细胞上的BMP-2/4/6表达显著高于纤维组织。此外，抑制性SMAD-6的表达仅在未钙化的脑室内皮细胞中显著表达。Smad-1/5/8在人AVs钙化的纤维内皮细胞中优先激活，与BMP拮抗剂和抑制性Smad6的低表达有关。这些结果表明，BMP拮抗剂在人动静脉侧向钙化中起主导作用。
Aortic valve (AV) calcification preferentially occurs on the fibrosa side while the ventricularis side remains relatively unaffected. Here, we tested the hypothesis that side-dependent activation of bone morphogenic protein (BMP) pathway in the endothelium of the ventricularis and fibrosa is associated with human AV calcification. Human calcified AVs obtained from AV replacement surgeries and non-calcified AVs from heart transplantations were used for immunohistochemical studies. We found SMAD-1/5/8 phosphorylation (a canonical BMP pathway) was higher in the calcified fibrosa than the non-calcified fibrosa while SMAD-2/3 phosphorylation (a canonical TGFβ pathway) did not show any difference. Interestingly, we found that BMP-2/4/6 expression was significantly higher on the ventricularis endothelium compared to the fibrosa in both calcified and non-calcified AV cusps; however, BMP antagonists (crossvienless-2/BMPER and noggin) expression was significantly higher on the ventricularis endothelium compared to the fibrosa in both disease states. Moreover, significant expression of inhibitory SMAD-6 expression was found only in the non-calcified ventricularis endothelium. SMAD-1/5/8 is preferentially activated in the calcified fibrosa endothelium of human AVs and it correlates with low expression of BMP antagonists and inhibitory SMAD6. These results suggest a dominant role of BMP antagonists in the side-dependent calcification of human AVs.
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DOI：
10.1111/j.1368-5031.2004.00219.x
发表时间：
2005-01-01
影响因子：
2.6
作者：
Hsu, SY;Hsieh, IC;Hung, KC
通讯作者：
Hung, KC
影响因子：
6.7
作者：
Koos, Ralf;Krueger, Thilo;Schurgers, Leon J.
通讯作者：
Schurgers, Leon J.
影响因子：
4.6
作者：
Jian, B;Narula, N;Levy, RJ
通讯作者：
Levy, RJ
影响因子：
56.9
作者：
NAKAMURA, T;TAKIO, K;SUGINO, H
通讯作者：
SUGINO, H
影响因子：
20.1
作者：
Simmons, CA;Grant, GR;Davies, PF
通讯作者：
Davies, PF