Diabetes Research Program, Division of Endocrinology, Department of Medicine, NYU School of Medicine, New York, NY 10016, USA.
Arterioscler Thromb Vasc Biol. 2013 Aug;33(8):1779-87. doi: 10.1161/ATVBAHA.112.301113. Epub 2013 Jun 13.
Subjects with diabetes mellitus are at high risk for developing atherosclerosis through a variety of mechanisms. Because the metabolism of glucose results in production of activators of protein kinase C (PKC)β, it was logical to investigate the role of PKCβ in modulation of atherosclerosis in diabetes mellitus.
ApoE(-/-) and PKCβ(-/-)/ApoE(-/-) mice were rendered diabetic with streptozotocin. Quantification of atherosclerosis, gene expression profiling, or analysis of signaling molecules was performed on aortic sinus or aortas from diabetic mice. Diabetes mellitus-accelerated atherosclerosis increased the level of phosphorylated extracellular signal-regulated kinase 1/2 and Jun-N-terminus kinase mitogen-activated protein kinases and augmented vascular expression of inflammatory mediators, as well as increased monocyte/macrophage infiltration and CD11c(+) cells accumulation in diabetic ApoE(-/-) mice, processes that were diminished in diabetic PKCβ(-/-)/ApoE(-/-) mice. In addition, pharmacological inhibition of PKCβ reduced atherosclerotic lesion size in diabetic ApoE(-/-) mice. In vitro, the inhibitors of PKCβ and extracellular signal-regulated kinase 1/2, as well as small interfering RNA to Egr-1, significantly decreased high-glucose-induced expression of CD11c (integrin, alpha X 9 complement component 3 receptor 4 subunit]), chemokine (C-C motif) ligand 2, and interleukin-1β in U937 macrophages.
These data link enhanced activation of PKCβ to accelerated diabetic atherosclerosis via a mechanism that includes modulation of gene transcription and signal transduction in the vascular wall, processes that contribute to acceleration of vascular inflammation and atherosclerosis in diabetes mellitus. Our results uncover a novel role for PKCβ in modulating CD11c expression and inflammatory response of macrophages in the development of diabetic atherosclerosis. These findings support PKCβ activation as a potential therapeutic target for prevention and treatment of diabetic atherosclerosis.
通过多种机制，糖尿病患者罹患动脉粥样硬化的风险很高。由于葡萄糖代谢导致蛋白激酶 C（PKC）β 的激活物产生，因此研究 PKCβ 在糖尿病中对动脉粥样硬化的调节作用是合理的。
用链脲佐菌素使载脂蛋白 E（-/-）和 PKCβ（-/-）/载脂蛋白 E（-/-）小鼠发生糖尿病。对糖尿病小鼠的主动脉窦或主动脉进行动脉粥样硬化定量、基因表达谱分析或信号分子分析。糖尿病加速的动脉粥样硬化增加了磷酸化细胞外信号调节激酶 1/2 和 Jun-N-末端激酶丝裂原活化蛋白激酶的水平，并增强了血管炎症介质的表达，以及增加了单核细胞/巨噬细胞浸润和 CD11c（+）细胞在糖尿病载脂蛋白 E（-/-）小鼠中的积聚，这些过程在糖尿病 PKCβ（-/-）/载脂蛋白 E（-/-）小鼠中减少。此外，PKCβ 的药理学抑制减少了糖尿病载脂蛋白 E（-/-）小鼠的动脉粥样硬化病变大小。在体外，PKCβ 和细胞外信号调节激酶 1/2 的抑制剂，以及 Egr-1 的小干扰 RNA，显著降低了高葡萄糖诱导的 U937 巨噬细胞中 CD11c（整合素，alpha X 9 补体成分 3 受体 4 亚基）、趋化因子（C-C 基序）配体 2 和白细胞介素-1β的表达。
这些数据将 PKCβ 的增强激活与通过调节血管壁中的基因转录和信号转导来加速糖尿病动脉粥样硬化联系起来，这些过程有助于加速糖尿病中血管炎症和动脉粥样硬化的发生。我们的结果揭示了 PKCβ 在调节糖尿病动脉粥样硬化发生中巨噬细胞 CD11c 表达和炎症反应中的新作用。这些发现支持 PKCβ 激活作为预防和治疗糖尿病动脉粥样硬化的潜在治疗靶点。
