Evidence for active regulation of pro-osteogenic signaling in advanced aortic valve disease.
Evidence for active regulation of pro-osteogenic signaling in advanced aortic valve disease.
复制标题
DOI：
10.1161/atvbaha.110.211029
复制
发表时间：
2010-12
期刊：
影响因子：
--
通讯作者：
Heistad DD
中科院分区：
文献类型：
--
作者：
Miller JD;Weiss RM;Serrano KM;Castaneda LE;Brooks RM;Zimmerman K;Heistad DD
本研究验证了在患有晚期主动脉瓣疾病的小鼠中瓣膜钙沉积、促成骨信号传导和功能可以改变的假设。“Reversa”小鼠被置于西式饮食12个月，并筛选是否存在主动脉瓣狭窄。将患有晚期瓣膜疾病的小鼠分为两组：1）持续进展2个月，和2）“消退”2个月，其中通过“遗传开关”实现脂质降低。对照组小鼠14个月内胆固醇正常。患有晚期瓣膜疾病的小鼠具有大量瓣膜钙化，其与骨形态发生蛋白信号传导、Wnt/β-连环蛋白信号传导和成骨细胞样细胞分化标志物的增加相关。值得注意的是，用“基因开关”降低血浆脂质显著减少了促成骨信号的标志物，并显著减少了瓣膜钙沉积。然而，尽管瓣膜钙沉积显著减少，瓣膜功能仍然明显受损。磷酸化Smad 2水平和肌成纤维细胞活化（促纤维化信号传导的指数）保持升高。在主动脉瓣狭窄的终末期，导致瓣膜钙化和成骨的分子过程仍然非常不稳定。虽然瓣膜钙沉积的减少不足以改善我们动物的瓣膜功能，但这些发现表明，主动脉瓣钙化是一个显着的动态过程，即使在存在晚期主动脉瓣疾病的情况下，也可以进行治疗。
This study tested the hypothesis that valvular calcium deposition, pro-osteogenic signaling, and function can be altered in mice with advanced aortic valve disease. “Reversa” mice were placed on a Western-type diet for 12 months and screened for the presence of aortic valve stenosis. Mice with advanced valve disease were assigned to two groups: 1) continued progression for 2 months, and 2) “regression” for 2 months, in which lipid lowering was accomplished by a “genetic switch”. Control mice were normocholesterolemic for 14 months. Mice with advanced valve disease had massive valvular calcification that was associated with increases in bone morphogenetic protein signaling, Wnt/β-catenin signaling, and markers of osteoblast-like cell differentiation. Remarkably, reducing plasma lipids with a “genetic switch” dramatically reduced markers of pro-osteogenic signaling and significantly reduced valvular calcium deposition. Nevertheless, despite a marked reduction in valvular calcium deposition, valve function remained markedly impaired. Phospho-Smad2 levels and myofibroblast activation (indices of pro-fibrotic signaling) remained elevated. Molecular processes that contribute to valvular calcification and osteogenesis remain remarkably labile during end stages of aortic valve stenosis. While reductions in valvular calcium deposition were not sufficient to improve valvular function in our animals, these findings demonstrate that aortic valve calcification is a remarkably dynamic process that can be modified therapeutically even in the presence of advanced aortic valve disease.