Monzack Elyssa L, Gu Xiaoxiao, Masters Kristyn S
Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA.
Arterioscler Thromb Vasc Biol. 2009 Feb;29(2):246-53. doi: 10.1161/ATVBAHA.108.179218. Epub 2008 Nov 20.
The lack of therapies that inhibit valvular calcification and the conflicting outcomes of clinical studies regarding the impact of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors on valve disease highlight the need for controlled investigations to characterize the interactions between HMG-CoA reductase inhibitors and valve tissue. Thus, we applied multiple in vitro disease stimuli to valvular interstitial cell (VIC) cultures and examined the impact of simvastatin treatment on VIC function.
VICs were cultured on 3 different substrates that supported various levels of nodule formation. Transforming growth factor (TGF)-beta1 was also applied as a disease stimulus to VICs on 2-D surfaces or encapsulated in 3-D collagen gels and combined with different temporal applications of simvastatin. Simvastatin inhibited calcific nodule formation in a dose-dependent manner on all materials, although the level of statin efficacy was highly substrate-dependent. Simvastatin treatment significantly altered nodule morphology, resulting in dramatic nodule dissipation over time, also in a substrate-dependent manner. These effects were mimicked in 3-D cultures, wherein simvastatin reversed TGF-beta1-induced contraction. Decreases in nodule formation were not achieved via the HMG-CoA reductase pathway, but were correlated with decreases in ROCK activity.
These studies represent a significant contribution to understanding how simvastatin may impact heart valve calcification.
缺乏抑制瓣膜钙化的治疗方法，以及关于3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂对瓣膜疾病影响的临床研究结果相互矛盾，这凸显了进行对照研究以表征HMG-CoA还原酶抑制剂与瓣膜组织之间相互作用的必要性。因此，我们对瓣膜间质细胞（VIC）培养物施加了多种体外疾病刺激，并研究了辛伐他汀治疗对VIC功能的影响。
将VIC培养在3种不同的支持不同结节形成水平的基质上。还将转化生长因子（TGF）-β1作为疾病刺激物施加于二维表面上或封装在三维胶原凝胶中的VIC，并与不同时间应用的辛伐他汀联合使用。辛伐他汀在所有材料上均以剂量依赖性方式抑制钙化结节形成，尽管他汀类药物的疗效水平高度依赖于基质。辛伐他汀治疗显著改变了结节形态，导致结节随时间显著消散，同样呈基质依赖性。这些效应在三维培养物中得以模拟，其中辛伐他汀逆转了TGF-β1诱导的收缩。结节形成的减少并非通过HMG-CoA还原酶途径实现，而是与ROCK活性的降低相关。
这些研究对理解辛伐他汀如何影响心脏瓣膜钙化做出了重要贡献。
