Department of Surgery, University of Colorado Denver, Aurora, CO 80045, USA.
Arterioscler Thromb Vasc Biol. 2012 Nov;32(11):2711-20. doi: 10.1161/ATVBAHA.112.300116. Epub 2012 Sep 13.
Although biglycan (BGN) and oxidized low-density lipoprotein (oxLDL) accumulation has been observed in calcific, stenotic aortic valves, their role in the pathogenesis of calcific aortic valve disease is poorly understood. We hypothesized that soluble BGN induces the osteogenic response in human aortic valve interstitial cells via Toll-like receptor (TLR) 2 and TLR4 and mediates the proosteogenic effect of oxLDL.
Aortic valve interstitial cells of stenotic valves express higher levels of BGN. Stimulation of cells from normal valves with BGN increased the expression of bone morphogenetic protein-2 (BMP-2) and alkaline phosphatase (ALP) among the chondrogenic/osteogenic markers examined and caused accumulation of calcium deposits. TLR2 silencing, but not TLR4 silencing, reduced BMP-2 and ALP levels after BGN stimulation although coimmunoprecipitation revealed that BGN interacts with both TLR2 and TLR4. BGN induced the phosphorylation of extracellular signal-regulated protein kinase-1/2, p38 mitogen-activated protein kinase and nuclear factor-κB. Inhibition of extracellular-regulated kinase-1/2 markedly reduced the upregulation of BMP-2 and ALP expression by BGN whereas inhibition of p38 mitogen-activated protein kinase or nuclear factor-κB had a moderate effect. Stimulation of aortic valve interstitial cells with oxLDL upregulated BGN expression and release. Knockdown and neutralization of BGN reduced the effect of oxLDL on BMP-2 and ALP expression.
Extracellular soluble BGN induces the expression of BMP-2 and ALP in human aortic valve interstitial cells primarily via TLR2 and contributes to the proosteogenic effect of oxLDL. These findings highlight the potential role of soluble BGN and oxLDL in the development of calcific aortic valve disease.
尽管在钙化性狭窄主动脉瓣中观察到 biglycan（BGN）和氧化型低密度脂蛋白（oxLDL）的积累，但它们在钙化性主动脉瓣疾病发病机制中的作用仍知之甚少。我们假设可溶性 BGN 通过 Toll 样受体（TLR）2 和 TLR4 诱导人主动脉瓣间质细胞的成骨反应，并介导 oxLDL 的促成骨作用。
狭窄瓣膜的主动脉瓣间质细胞表达更高水平的 BGN。用 BGN 刺激来自正常瓣膜的细胞，增加了所检查的软骨/成骨标志物中的骨形态发生蛋白-2（BMP-2）和碱性磷酸酶（ALP）的表达，并导致钙沉积的积累。TLR2 沉默，但不是 TLR4 沉默，降低了 BGN 刺激后的 BMP-2 和 ALP 水平，尽管共沉淀显示 BGN 与 TLR2 和 TLR4 相互作用。BGN 诱导细胞外信号调节激酶-1/2、p38 丝裂原活化蛋白激酶和核因子-κB 的磷酸化。细胞外调节激酶-1/2 的抑制显著降低了 BGN 对 BMP-2 和 ALP 表达的上调作用，而 p38 丝裂原活化蛋白激酶或核因子-κB 的抑制作用则具有适度的作用。oxLDL 刺激主动脉瓣间质细胞上调 BGN 的表达和释放。BGN 的敲低和中和降低了 oxLDL 对 BMP-2 和 ALP 表达的作用。
细胞外可溶性 BGN 主要通过 TLR2 诱导人主动脉瓣间质细胞中 BMP-2 和 ALP 的表达，并有助于 oxLDL 的促成骨作用。这些发现强调了可溶性 BGN 和 oxLDL 在钙化性主动脉瓣疾病发展中的潜在作用。
