Progression of aortic valve stenosis:: TGF-β1 is present in calcified aortic valve cusps and promotes aortic valve interstitial cell calcification via apoptosis
Progression of aortic valve stenosis:: TGF-β1 is present in calcified aortic valve cusps and promotes aortic valve interstitial cell calcification via apoptosis
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DOI：
10.1016/s0003-4975(02)04312-6
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发表时间：
2003-02-01
影响因子：
4.6
通讯作者：
Levy, RJ
中科院分区：
文献类型：
--
作者：
Jian, B;Narula, N;Levy, RJ
背景。主动脉瓣狭窄通常由于瓣尖钙化而进展，往往需要进行瓣膜置换手术。本研究验证了这样一个假说，即转化生长因子 -β1（一种在培养中可导致血管平滑肌细胞钙化的细胞因子）引发瓣膜间质细胞凋亡，这是瓣尖钙化的一个机制性事件。
方法。在尸检或心脏手术时获取未钙化和钙化的人主动脉瓣瓣尖。利用免疫组织化学方法研究转化生长因子 -β1、潜在转化生长因子 -β1相关肽以及转化生长因子受体在瓣尖内的分布。还利用绵羊主动脉瓣间质细胞（SAVIC）培养来研究转化生长因子 -β1对导致主动脉瓣钙化的机制性事件的影响。
结果。免疫组织化学研究显示，钙化性主动脉瓣狭窄瓣尖在细胞外基质中所含的转化生长因子 -β1在质量上比未钙化瓣尖更高。未钙化的正常瓣膜仅显示局灶性细胞内转化生长因子 -β1。向SAVIC培养物中添加转化生长因子 -β1导致一系列事件，包括：细胞迁移、聚集、形成富含凋亡 - 碱性磷酸酶的结节以及这些结节的钙化。在SAVIC培养系统中，这些事件的时间进程很快，72小时出现伴有凋亡的结节形成，7天后出现钙化。此外，ZVAD - FMK（一种抗凋亡剂，即半胱天冬酶抑制剂）显著抑制由转化生长因子 -β1诱导的钙化和凋亡，但对结节形成没有影响。然而，细胞松弛素D（一种肌动蛋白解聚剂）抑制结节形成，但不抑制钙化。
结论。转化生长因子 -β1特征性地存在于钙化性主动脉瓣狭窄瓣尖内，并通过涉及凋亡的机制介导培养中的主动脉瓣间质细胞钙化。（C）2003年，胸外科医师协会。
Background. Aortic valve stenosis characteristically progresses due to cuspal calcification, often necessitating valve replacement surgery. The present study investigated the hypothesis that TGF-beta1, a cytokine that causes calcification of vascular smooth muscle cells in culture, initiates apoptosis of valvular interstitial cells as a mechanistic event in cuspal calcification.Methods. Noncalcified and calcified human aortic valve cusps were obtained at autopsy or at the time of cardiac surgery. The distributions within cusps of TGF-beta1, latent-TGF-beta1-associated peptide, and TGF-beta receptors were studied using immunohistochemistry. The effects of TGF-beta1 on mechanistic events contributing to aortic valve calcification were also investigated using sheep aortic valve interstitial cell (SAVIC) cultures.Results. Immunohistochemistry studies revealed that calcific aortic stenosis cusps characteristically contained within the extracellular matrix qualitatively higher levels of TGF-beta1 than noncalcified cusps. Noncalcified normal valves demonstrated only focal intracellular TGF-beta1. Addition of TGF-beta1 to SAVIC cultures led to a cascade of events, including: cellular migration, aggregation, formation of apoptotic-alkaline phosphatase enriched nodules, and calcification of these nodules. The time course of these events in the SAVIC culture system was rapid with nodule formation with apoptosis by 72 hours, and calcification after 7 days. Furthermore, ZVAD-FMK, an antiapoptosis agent (caspase inhibitor), significantly inhibited calcification and apoptosis induced by TGF-beta1, but had no effect on nodule formation. However, cytochalasin D, an actin-depolymerizing agent, inhibited nodule formation, but not calcification.Conclusions. TGF-beta1 is characteristically present within calcitic aortic stenosis cusps, and mediates the calcification of aortic valve interstitial cells in culture through mechanisms involving apoptosis. (C) 2003 by The Society of Thoracic Surgeons.