Statins block calcific nodule formation of valvular interstitial cells by inhibiting alpha-smooth muscle actin expression.
Statins block calcific nodule formation of valvular interstitial cells by inhibiting alpha-smooth muscle actin expression.
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DOI：
10.1161/atvbaha.109.195271
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发表时间：
2009-11
期刊：
影响因子：
--
通讯作者：
Anseth KS
中科院分区：
文献类型：
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作者：
Benton JA;Kern HB;Leinwand LA;Mariner PD;Anseth KS
以过度纤维化和骨样钙化组织沉积为特征的钙化性主动脉瓣狭窄影响约2-3%的65岁以上美国人群。最近的研究表明，他汀类药物对主动脉狭窄的进展有积极的影响，可能是由于他们能够影响居民细胞群，称为瓣膜间质细胞（VIC）。VIC是成纤维细胞，可分化形成活化的肌成纤维细胞，表现出增加的α平滑肌肌动蛋白（αSMA）表达、收缩性和胶原蛋白产生。在培养中，VIC自发形成多细胞聚集体，随后发展成钙化结节，为主动脉瓣狭窄提供了体外模型。使用实时显微镜跟踪，我们观察到汇合的维克单层自发收缩成圆形结节，这表明肌成纤维细胞的收缩性是结节形成过程中的关键步骤。αSMA的过表达增加了维克钙化结节的形成和收缩性，而用siRNA敲低αSMA则减少了这些表型，这表明αSMA的表达和收缩特性对结节的形成至关重要。VIC的他汀类药物治疗减少αSMA表达，抑制收缩性，并减少结节形成。当他汀类药物用于治疗预先形成的结节时，没有观察到钙化结节数量的减少，这表明他汀类药物在主动脉瓣狭窄中可能发挥更多的预防作用而不是治疗作用。我们的研究提供了维克肌成纤维细胞活性和初始维克钙化结节形成之间因果关系的证据。此外，我们证明普伐他汀抑制钙化结节的形成与抑制肌成纤维细胞活性有关。
Calcific aortic stenosis, characterized by excessive fibrosis and deposition of bone-like calcified tissue, affects roughly 2–3% of the US population over 65. Recent studies have suggested that statins have a positive effect on the progression of aoritic stenosis, likely due to their ability to affect the resident cell population, known as valvular interstitial cells (VICs). VICs are fibroblastic cells that can differentiate to form activated myofibroblasts, displaying increased alpha smooth muscle actin (αSMA) expression, contractility, and collagen production. In culture, VICs spontaneously form multicellular aggregates that subsequently develop into calcified nodules, providing an in vitro model for aortic stenosis. Using real-time microscopic tracking, we observed that confluent VIC monolayers spontaneously contract into rounded nodules, suggesting that myofibroblastic contractility is a critical step in the process of nodule formation. Over-expression of αSMA increased VIC calcific nodule formation and contractility, while knock-down of αSMA with siRNAs reduced these phenotypes, suggesting that the expression and contractile properties of αSMA are essential to the formation of nodules. Statin treatment of VICs reduced αSMA expression, inhibited contractility, and decreased nodule formation. When statins were used to treat preformed nodules, no decrease in the number of calcified nodules was observed, suggesting that statins may play more of a preventative role in aortic stenosis than a cure. Our studies provide evidence of a causal relationship between VIC myofibroblastic activity and initial VIC calcific nodule formation. Furthermore we demonstrate that pravastatin inhibition of calcific nodule formation is related to inhibition of myofibroblastic activity.