Abnormal High-Density Lipoprotein Induces Endothelial Dysfunction via Activation of Toll-like Receptor-2

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• 作者：Thimoteus Speer¹ ; ² ; ⁹ ; ^{timo.speer@uks.eu} ; Lucia Rohrer⁴ ; ⁵ ; ⁹ ; Przemyslaw Blyszczuk¹ ; Rukshana Shroff⁶ ; ⁷ ; Kira Kuschnerus¹ ; Nicolle Krä ; nkel¹ ; Gabriela Kania¹ ; Stephen Zewinger² ; Alexander Akhmedov¹ ; Yi Shi¹ ; Tina Martin² ; Damir Perisa⁵ ; Stephan Winnik¹ ; Maja F. Mü ; ller¹ ; Urban Sester² ; Gabriel Wernicke² ; Andreas Jung² ; Ursula Gutteck⁵ ; Urs Eriksson¹ ; ⁸ ; Jü ; rgen Geisel³ ; John Deanfield⁷ ; Arnold von Eckardstein⁴ ; ⁵ ; Thomas F. Lü ; scher¹ ; ⁴ ; Danilo Fliser² ; Ferdinand H. Bahlmann² ; Ulf Landmesser¹ ; ⁴
• 刊名：Immunity
• 出版年：2013
• 出版时间：18 April, 2013
• 年：2013
• 卷：38
• 期：4
• 页码：754-768
• 全文大小：1322 K

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Summary

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 (HDL^CKD), a population with high cardiovascular risk, we have demonstrated that HDL^CKD in contrast to HDL^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 HDL^CKD that causes transformation from physiological HDL into an abnormal lipoprotein inducing ED. Furthermore, we report that HDL^CKD 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.