Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA.
Am J Physiol Heart Circ Physiol. 2012 Oct 1;303(7):H903-9. doi: 10.1152/ajpheart.00263.2012. Epub 2012 Aug 17.
Statin drugs are prescribed primarily for their ability to lower cholesterol, but may also exert beneficial side effects unrelated to cholesterol metabolism. Previous work has described a "statin paradox," where statin treatment decreased osteoblastic markers in valve myofibroblasts while increasing those same markers in preosteoblasts. However, valvular interstitial cells (VICs) themselves are a multipotent cell type, capable of differentiating into activated, myofibroblastic VICs (aVICs) and osteoblastic VICs (obVICs), motivating the question of whether the statin paradox can exist within an individual valve containing these phenotypically distinct VIC subpopulations. In the current study, a heterogeneous initial population of porcine VICs was differentiated into aVICs or obVICs and treated with simvastatin. Gene expression analysis was conducted daily over an 8-day time course to capture temporally dynamic changes in cell phenotype induced by statin treatment. These studies demonstrated that the two VIC populations, aVICs and obVICs, exhibited differential responses to statin treatment. Specifically, simvastatin increased the expression of osteoblastic markers in obVICs, but not in aVICs, while also suppressing the myofibroblastic phenotype in both aVICs and obVICs. These results indicate that the statin paradox can exist within the heterogeneous VIC population of an individual diseased valve and that statin efficacy in the context of calcific aortic valve disease (CAVD) may be dependent upon the cellular composition of the valve. These findings may have implications for clinical usage of statins, shedding light on how statin efficacy in CAVD may be dependent upon the disease stage or why some individuals exhibit better responsiveness to statin therapy.
他汀类药物主要因其降低胆固醇的能力而被开处方，但也可能发挥与胆固醇代谢无关的有益副作用。先前的工作描述了一种“他汀类药物悖论”，即他汀类药物治疗降低了瓣膜成纤维细胞中的成骨细胞标记物，同时增加了前成骨细胞中的这些标记物。然而，瓣膜间质细胞（VIC）本身是一种多能细胞类型，能够分化为激活的成纤维细胞样 VIC（aVIC）和成骨细胞样 VIC（obVIC），这就提出了一个问题，即在含有这些表型不同的 VIC 亚群的单个瓣膜中，他汀类药物悖论是否存在。在本研究中，猪 VIC 的异质初始群体被分化为 aVIC 或 obVIC，并接受辛伐他汀治疗。在 8 天的时间过程中，每天进行基因表达分析，以捕获他汀类药物治疗诱导的细胞表型的时间动态变化。这些研究表明，两种 VIC 群体，aVIC 和 obVIC，对他汀类药物治疗表现出不同的反应。具体而言，辛伐他汀增加了 obVIC 中成骨细胞标记物的表达，但在 aVIC 中则没有，同时抑制了 aVIC 和 obVIC 中的成纤维细胞样表型。这些结果表明，他汀类药物悖论可以存在于个体患病瓣膜的异质 VIC 群体中，并且他汀类药物在钙化性主动脉瓣疾病（CAVD）中的疗效可能取决于瓣膜的细胞组成。这些发现可能对他汀类药物的临床应用具有重要意义，阐明了 CAVD 中他汀类药物的疗效如何可能取决于疾病阶段，或者为什么有些个体对他汀类药物治疗有更好的反应。
