From Laboratoire d'Études Moléculaires des Valvulopathies (LEMV), Groupe de Recherche en Valvulopathies (GRV), Quebec Heart and Lung Institute/Research Center, Department of Surgery (R.B., A.M., M.J.N., M.-C.B., J.-L.L., M.-H.L., F.H., P.M.), Department of Medicine (A.D., P.P., B.J.A., A.M.), Department of Pathology (C.C., S.T., S.P.), and Department of Molecular Medicine (Y.B.), Laval University, Québec, Canada; and Department of Chemistry and Biochemistry, University of Windsor, Ontario, Canada (C.A.S., R.R., M.L.K.).
Circulation. 2015 Aug 25;132(8):677-90. doi: 10.1161/CIRCULATIONAHA.115.016757. Epub 2015 Jul 29.
Mendelian randomization studies have highlighted that lipoprotein(a) [Lp(a)] was associated with calcific aortic valve disease (CAVD). Lp(a) transports oxidized phospholipids with a high content in lysophosphatidylcholine. Autotaxin (ATX) transforms lysophosphatidylcholine into lysophosphatidic acid. We hypothesized that ATX-lysophosphatidic acid could promote inflammation/mineralization of the aortic valve.
We have documented the expression of ATX in control and mineralized aortic valves. By using different approaches, we have also investigated the role of ATX-lysophosphatidic acid in the mineralization of isolated valve interstitial cells and in a mouse model of CAVD. Enzyme-specific ATX activity was elevated by 60% in mineralized aortic valves in comparison with control valves. Immunohistochemistry studies showed a high level of ATX in mineralized aortic valves, which colocalized with oxidized phospholipids and apolipoprotein(a). We detected a high level of ATX activity in the Lp(a) fraction in circulation. Interaction between ATX and Lp(a) was confirmed by in situ proximity ligation assay. Moreover, we documented that valve interstitial cells also expressed ATX in CAVD. We showed that ATX-lysophosphatidic acid promotes the mineralization of the aortic valve through a nuclear factor κB/interleukin 6/bone morphogenetic protein pathway. In LDLR(-/-)/ApoB(100/100)/IGFII mice, ATX is overexpressed and lysophosphatidic acid promotes a strong deposition of hydroxyapatite of calcium in aortic valve leaflets and accelerates the development of CAVD.
ATX is transported in the aortic valve by Lp(a) and is also secreted by valve interstitial cells. ATX-lysophosphatidic acid promotes inflammation and mineralization of the aortic valve and thus could represent a novel therapeutic target in CAVD.
孟德尔随机化研究表明脂蛋白(a)[Lp(a)]与钙化性主动脉瓣疾病（CAVD）有关。Lp(a) 携带富含溶血磷脂酰胆碱的氧化磷脂。自分泌酶（ATX）将溶血磷脂酰胆碱转化为溶血磷脂酸。我们假设 ATX-溶血磷脂酸可以促进主动脉瓣的炎症/矿化。
我们记录了 ATX 在对照和矿化主动脉瓣中的表达。通过使用不同的方法，我们还研究了 ATX-溶血磷脂酸在分离的瓣膜间质细胞矿化和 CAVD 小鼠模型中的作用。与对照瓣膜相比，矿化主动脉瓣中的 ATX 酶活性升高了 60%。免疫组织化学研究显示，矿化主动脉瓣中 ATX 水平较高，与氧化磷脂和载脂蛋白(a) 共定位。我们在循环中的 Lp(a) 部分检测到高水平的 ATX 活性。原位邻近连接测定证实了 ATX 与 Lp(a) 的相互作用。此外，我们记录到 CAVD 中的瓣膜间质细胞也表达 ATX。我们表明，ATX-溶血磷脂酸通过核因子 κB/白细胞介素 6/骨形态发生蛋白途径促进主动脉瓣的矿化。在 LDLR(-/-)/ApoB(100/100)/IGFII 小鼠中，ATX 过表达，溶血磷脂酸促进主动脉瓣叶中羟基磷灰石钙的大量沉积，并加速 CAVD 的发展。
ATX 由 Lp(a) 在主动脉瓣中转运，也由瓣膜间质细胞分泌。ATX-溶血磷脂酸促进主动脉瓣的炎症和矿化，因此可能成为 CAVD 的新治疗靶点。
