Department of Pharmacology and Therapeutic Innovation, Nagasaki University Graduate School of Biomedical Sciences, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
Institute for Biomedical Sciences, Shinshu University Interdisciplinary Cluster for Cutting Edge Research 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan.
Mol Cell Endocrinol. 2018 Sep 15;473:100-113. doi: 10.1016/j.mce.2018.01.008. Epub 2018 Jan 20.
Alkyl-glycerophosphate (AGP) accumulates in atherogenic oxidized-LDL and human atherosclerotic plaques and is a potent agonist of peroxisome-proliferator-activated receptor-gamma (PPARγ). Recent studies suggest a potential regulatory role for PPARγ in endothelial nitric oxide synthase (eNOS) expression/activation and nitrogen oxide (NO) generation in the vascular endothelium. Importantly, eNOS-induced NO and advanced glycation end-products (AGEs) are involved in blood-vessel damage, and diabetic patients exhibit high serum NO and AGE levels; however, the effect of AGP on NO- and AGE-mediated endothelium dysfunction remains unknown. Investigation of the AGP-specific effects on NO- and AGE-mediated dysfunction and the underlying molecular mechanisms revealed that AGP upregulated eNOS expression and NO production, and that eNOS silencing and PPARγ antagonism inhibited AGP-mediated eNOS upregulation and NO production. Moreover, AGP-PPARγ-axis-mediated NO production promoted the generation of reactive oxygen species and AGE formation. These results suggested that AGP plays a significant role in the initiation/progression of diabetes-related atherosclerosis through PPARγ activation.
烷基甘油磷酸酯 (AGP) 在动脉粥样硬化氧化 LDL 和人类动脉粥样斑块中积累，是过氧化物酶体增殖物激活受体-γ (PPARγ) 的有效激动剂。最近的研究表明，PPARγ 在血管内皮细胞中内皮型一氧化氮合酶 (eNOS) 的表达/激活和氮氧化物 (NO) 生成中可能具有调节作用。重要的是，eNOS 诱导的 NO 和晚期糖基化终产物 (AGEs) 参与血管损伤，糖尿病患者表现出高血清 NO 和 AGE 水平；然而，AGP 对 NO 和 AGE 介导的内皮功能障碍的影响尚不清楚。研究 AGP 对 NO 和 AGE 介导的功能障碍的特异性作用及其潜在的分子机制表明，AGP 上调了 eNOS 的表达和 NO 的产生，而 eNOS 沉默和 PPARγ 拮抗剂抑制了 AGP 介导的 eNOS 上调和 NO 的产生。此外，AGP-PPARγ 轴介导的 NO 产生促进了活性氧和 AGE 形成。这些结果表明，AGP 通过激活 PPARγ 在糖尿病相关动脉粥样硬化的发生/进展中发挥重要作用。
