Abnormal High-Density Lipoprotein Induces Endothelial Dysfunction via Activation of Toll-like Receptor-2
Abnormal High-Density Lipoprotein Induces Endothelial Dysfunction via Activation of Toll-like Receptor-2
复制标题
DOI：
10.1016/j.immuni.2013.02.009
复制
发表时间：
2013-04-18
期刊：
影响因子：
32.4
通讯作者：
Landmesser, Ulf
中科院分区：
文献类型：
--
作者：
Speer, Thimoteus;Rohrer, Lucia;Landmesser, Ulf
内皮损伤和功能障碍(ED)代表了促进高血压的心血管危险因素和动脉粥样硬化之间的联系，动脉粥样硬化是西方人口的主要死亡原因。高密度脂蛋白(高密度脂蛋白)被认为是抗动脉粥样硬化和已知的预防ED的药物。使用儿童和成人慢性肾功能不全(HDLCKD)患者的高密度脂蛋白(HDLCKD)，这是一种心血管风险高的人群，我们已经证明，与高密度脂蛋白(健康)相比，HDLCKD促进内皮超氧化物的产生，显著降低一氧化氮(NO)的生物利用度，并随后升高动脉血压(ABP)。我们已经在HDLCKD中发现了对称性二甲基精氨酸(SDMA)，它能引起生理性高密度脂蛋白向异常脂蛋白的转化，从而导致ED。此外，我们报告了HDLCKD通过Toll样受体-2(TLR-2)减少内皮NO的可获得性，导致内皮修复受损，促炎活性增加，以及ABP。这些数据表明，SDMA如何修饰高密度脂蛋白颗粒，以模拟损伤相关的分子模式，通过TLR-1或TLR-6共受体非依赖性途径激活TLR-2，将异常的高密度脂蛋白与先天性免疫、ED和高血压联系起来。
Endothelial injury and dysfunction (ED) represent a link between cardiovascular risk factors promoting hypertension and atherosclerosis, the leading cause of death in Western populations. High-density lipoprotein (HDL) is considered antiatherogenic and known to prevent ED. Using HDL from children and adults with chronic kidney dysfunction (HDLCKD), a population with high cardiovascular risk, we have demonstrated that HDLCKD incontrast toHDL(Healthy) promoted endothelial superoxide production, substantially reduced nitric oxide (NO) bioavailability, and subsequently increased arterial blood pressure (ABP). We have identified symmetric dimethylarginine (SDMA) in HDLCKD that causes transformation from physiological HDL into an abnormal lipoprotein inducing ED. Furthermore, we report that HDLCKD reduced endothelial NO availability via toll-like receptor-2 (TLR-2), leading to impaired endothelial repair, increased proinflammatory activation, and ABP. These data demonstrate how SDMA can modify the HDL particle to mimic a damage-associated molecular pattern that activates TLR-2 via a TLR-1- or TLR-6-coreceptor-independent pathway, linking abnormal HDL to innate immunity, ED, and hypertension.