Autotaxin Derived From Lipoprotein(a) and Valve Interstitial Cells Promotes Inflammation and Mineralization of the Aortic Valve
Autotaxin Derived From Lipoprotein(a) and Valve Interstitial Cells Promotes Inflammation and Mineralization of the Aortic Valve
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DOI：
10.1161/circulationaha.115.016757
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发表时间：
2015-08-25
期刊：
影响因子：
37.8
通讯作者：
Mathieu, Patrick
中科院分区：
文献类型：
--
作者：
Bouchareb, Rihab;Mahmut, Ablajan;Mathieu, Patrick
背景孟德尔随机研究强调脂蛋白（a）[Lp（a）]与钙化性主动脉瓣疾病（CAVD）相关。脂蛋白（a）转运溶血磷脂酰胆碱含量高的氧化磷脂。自分泌运动因子（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炎症/矿化的主动脉valve.Methods和结果，我们已经记录了ATX的表达在控制和矿化的主动脉瓣。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，矿化主动脉瓣中酶特异性ATX活性升高60%。免疫组织化学研究显示，矿化主动脉瓣中存在高水平的ATX，其与氧化磷脂和载脂蛋白（a）共定位。我们在循环中的Lp（a）组分中检测到高水平的ATX活性。ATX与Lp（a）之间的相互作用通过原位邻位连接测定来证实。此外，我们证明，瓣膜间质细胞也表达ATX在CAVD。我们发现ATX-溶血磷脂酸通过核因子B/白细胞介素6/骨形态发生蛋白途径促进主动脉瓣矿化。LDLR-/-/ApoB（100/100）/IGFII小鼠主动脉瓣内ATX过表达，溶血磷脂酸可促进主动脉瓣内羟基磷灰石或钙的大量沉积，加速CAVD的发生发展。结论ATX通过Lp（a）在主动脉瓣内转运，也可由主动脉瓣间质细胞分泌。ATX-溶血磷脂酸促进主动脉瓣的炎症和矿化，因此可能代表CAVD的新治疗靶点。
Background 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.Methods and Results 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 B/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.Conclusions 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.