Durpès Marie-Claude, Morin Catherine, Paquin-Veillet Judith, Beland Raphaël, Paré Martin, Guimond Marie-Odile, Rekhter Mark, King George L, Geraldes Pedro
Research Center of the Centre Hospitalier Universitaire de Sherbrooke and Division of Endocrinology, Department of Medicine, Université de Sherbrooke, 3001 12e Avenue Nord, QC, Canada J1H 5N4.
Cardiometabolic Diseases and Complications of Diabetes, Lilly Research Laboratories, Indianapolis, IN, USA.
Cardiovasc Res. 2015 May 1;106(2):303-13. doi: 10.1093/cvr/cvv107. Epub 2015 Mar 24.
Clinical observations showed a correlation between accelerated atherosclerosis in diabetes and high plasmatic level of IL-18, a pro-inflammatory cytokine. IL-18 enhances the production of inflammatory cytokines and cellular adhesion molecules contributing to atherosclerotic plaque formation and instability. Previous studies indicated that protein kinase C (PKC)-β inhibition prevented macrophage-induced cytokine expression involved in diabetic (DM) atherosclerotic plaque development. However, the role of PKC-β activation on IL-18/IL-18-binding protein (IL-18BP) pathway causing endothelial dysfunction and monocyte adhesion in diabetes has never been explored.
Apoe(-/-) mice were rendered DM and fed with western diet containing ruboxistaurin (RBX), a PKC-β inhibitor. After 20 weeks, atherosclerotic plaque composition was quantified. Compared with non-diabetic, DM mice exhibited elevated atherosclerotic plaque formation, cholestoryl ester content and macrophage infiltration, as well as reduced IL-18BP expression in the aorta which was prevented with RBX treatment. Endothelial cells (ECs) and macrophages were exposed to normal or high glucose (HG) levels with or without palmitate and recombinant IL-18 for 24 h. The combined HG and palmitate condition was required to increase IL-18 expression and secretion in macrophages, while it reduced IL-18BP expression in EC causing up-regulation of the vascular cell adhesion molecule (VCAM)-1 and monocyte adhesion. Elevated VCAM-1 expression and monocyte adherence were prevented by siRNA, RBX, and IL-18 neutralizing antibody.
Our study unrevealed a new mechanism by which PKC-β activation promotes EC dysfunction caused by the de-regulation of the IL-18/IL-18BP pathway, leading to increased VCAM-1 expression, monocyte/macrophage adhesion, and accelerated atherosclerotic plaque formation in diabetes.
临床观察显示，糖尿病患者动脉粥样硬化加速与促炎细胞因子白细胞介素-18（IL-18）的高血浆水平之间存在相关性。IL-18可增强炎症细胞因子和细胞黏附分子的产生，促进动脉粥样硬化斑块的形成和不稳定。先前的研究表明，蛋白激酶C（PKC）-β抑制可阻止巨噬细胞诱导的细胞因子表达，而细胞因子表达参与糖尿病（DM）动脉粥样硬化斑块的发展。然而，PKC-β激活对糖尿病中导致内皮功能障碍和单核细胞黏附的IL-18/IL-18结合蛋白（IL-18BP）途径的作用从未被探讨过。
将载脂蛋白E基因敲除（Apoe(-/-)）小鼠诱导为糖尿病模型，并用含鲁伯斯塔林（RBX，一种PKC-β抑制剂）的西式饮食喂养。20周后，对动脉粥样硬化斑块成分进行定量分析。与非糖尿病小鼠相比，糖尿病小鼠的动脉粥样硬化斑块形成、胆固醇酯含量和巨噬细胞浸润增加，同时主动脉中IL-18BP表达降低，而RBX治疗可预防这种情况。将内皮细胞（ECs）和巨噬细胞暴露于正常或高糖（HG）水平，同时添加或不添加棕榈酸酯和重组IL-18，持续24小时。需要高糖和棕榈酸酯共同作用才能增加巨噬细胞中IL-18的表达和分泌，而这会降低内皮细胞中IL-18BP的表达，导致血管细胞黏附分子（VCAM）-1上调和单核细胞黏附。小干扰RNA（siRNA）、RBX和IL-18中和抗体可阻止VCAM-1表达升高和单核细胞黏附。
我们的研究揭示了一种新机制，即PKC-β激活通过IL-18/IL-18BP途径失调促进内皮细胞功能障碍，导致糖尿病中VCAM-1表达增加、单核细胞/巨噬细胞黏附以及动脉粥样硬化斑块形成加速。
