Pathological Biochemistry, Department of Internal Medicine 3, Carl Gustav Carus Medical School, University of Technology Dresden, Fetscherstraße 74, 01307, Dresden, Germany,
Mol Cell Biochem. 2013 Nov;383(1-2):21-8. doi: 10.1007/s11010-013-1749-9. Epub 2013 Jul 14.
Hyperglycemia- and oxidative stress-induced modification of circulating lipoproteins is being increasingly recognized as an important pathogenetic factor for diabetic cardiovascular damages. This study was designed to investigate the impact of modified very low-density lipoprotein and high-density lipoprotein on phagocyte adhesion to endothelial cells and the involvement of scavenger receptor class B type 1 (SR-BI) in this process. Native lipoproteins were isolated by density gradient ultracentrifugation and in vitro glycoxidative or oxidative modification was performed in the presence of glucose or sodium hypochlorite, respectively. One hour co-incubation experiments with lipoproteins, freshly prepared polymorphonuclear leukocytes (PMN), and venous endothelial cells (HUVEC) were performed in the presence or absence of different scavenger receptors and signal transduction inhibitors. PMN adhesion to HUVEC was quantified fluorimetrically. We demonstrated that oxidized and glycoxidized lipoproteins promote adhesion of PMN to HUVEC from 1.5- to 2.5-fold with oxidized lipoproteins having the greatest effect. Treatment with the highly specific SR-BI inhibitor, BLT-1 produced substantial reduction of lipoprotein-induced adhesion to endothelial cells. Native and modified lipoproteins recruited extracellular signal-regulated kinase (ERK 1/2), p38 mitogen-activated protein kinase, and Janus kinase 2 as downstream signaling pathways for adhesion. From this study, it could be concluded that modification of lipoproteins plays a crucial role in atherosclerotic progression and SR-BI may be considered as a potential therapeutic target for the prevention of diabetic cardiovascular complications.
高血糖和氧化应激引起的循环脂蛋白修饰，正被越来越多地认为是糖尿病心血管损害的一个重要发病因素。本研究旨在探讨修饰的极低密度脂蛋白和高密度脂蛋白对吞噬细胞黏附内皮细胞的影响，以及该过程中清道夫受体 B 类 1 型（SR-BI）的作用。采用密度梯度超速离心法分离天然脂蛋白，并在存在葡萄糖或次氯酸钠的情况下进行体外糖基化或氧化修饰。在存在或不存在不同的清道夫受体和信号转导抑制剂的情况下，进行脂蛋白、新制备的多形核白细胞（PMN）和静脉内皮细胞（HUVEC）的 1 小时共孵育实验。通过荧光法定量PMN 黏附到 HUVEC 的情况。我们证明，氧化和糖基化的脂蛋白可促进 PMN 与 HUVEC 的黏附，氧化脂蛋白的作用最大，可使黏附增加 1.5-2.5 倍。用高特异性的 SR-BI 抑制剂 BLT-1 处理，可显著减少脂蛋白诱导的内皮细胞黏附。天然和修饰的脂蛋白募集细胞外信号调节激酶（ERK1/2）、p38 丝裂原活化蛋白激酶和 Janus 激酶 2 作为黏附的下游信号通路。从这项研究可以得出结论，脂蛋白的修饰在动脉粥样硬化的进展中起着至关重要的作用，而 SR-BI 可被视为预防糖尿病心血管并发症的潜在治疗靶点。
