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Elucidation of a novel causative factor and investigation of effective foods in atherosclerosis

动脉粥样硬化新致病因素的阐明和有效食品的研究

基本信息

批准号：
20700593
负责人：
ICHI Ikuyo
金额：
$ 2.66万
依托单位：
Nara Women's University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2008
资助国家：
日本
起止时间：
2008 至 2010
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20700593/
关键词：
動脈硬化酸化ストレス脂質セラミド糖尿病 LC-MS/MS 抗酸化脂質代謝

项目摘要

Oxidative stress has been implicated in the development and progression of atherosclerosis. Ceramide has been implicated in regulating cell cycle arrest, apoptosis, and cellular senescence, and serves as an intracellular second messenger in these processes. Our previous study showed that ceramide concentrations in human plasma had a significantly positive correlation with lipid markers that associated with atherosclerosis. In this study, due to reveal the association of oxidative stress and ceramide metabolism in animal, we examined that oxidative stress via CCl_4 administration induces the changes of ceramide metabolism in not only the liver but also other organs such as the kidney. Tissue ceramide levels were analyzed using electrospray tandem mass spectrometry (LC-MS/MS). Next, we investigated whether ceramide metabolism was altered in damaged tissues by STZ administration, and whether ceramide accumulation is correlated with the pathogenesis of diabetes-induced complications. Although no differences in hepatic ceramide levels were observed between the control and diabetic rats, plasma and renal ceramide levels were significantly increased by STZ administration. The activations of sphingomyelinases, which hydrolyze sphingomyelin into ceramide, induced the increase of ceramide during STZ administration in plasma. Thus, Our data support the view that the excess accumulation of ceramide via oxidative stress may play an important role in the pathogenesis related atherosclerosis.

氧化应激与动脉粥样硬化的发生和发展有关。神经酰胺参与调节细胞周期停滞、凋亡和细胞衰老，并在这些过程中充当细胞内第二信使。我们前期的研究表明，人血浆中神经酰胺浓度与动脉粥样硬化相关的脂质标志物呈显著正相关。本研究旨在揭示动物体内氧化应激与神经酰胺代谢的关系，研究CCl_4引起的氧化应激不仅引起肝脏神经酰胺代谢的变化，而且引起肾脏等其他器官神经酰胺代谢的变化。采用电喷雾串联质谱法（LC-MS/MS）分析组织神经酰胺水平。接下来，我们研究了STZ给药是否改变了受损组织中的神经酰胺代谢，以及神经酰胺积累是否与糖尿病诱导的并发症的发病机制相关。虽然对照组和糖尿病大鼠之间没有观察到肝脏神经酰胺水平的差异，但STZ给药显著增加了血浆和肾脏神经酰胺水平。在STZ给药期间，鞘磷脂酶（将鞘磷脂水解为神经酰胺）的激活诱导血浆中神经酰胺的增加。因此，我们的数据支持的观点，神经酰胺通过氧化应激过度积累可能在动脉粥样硬化相关的发病机制中发挥重要作用。