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

氧化应激参与动脉粥样硬化的发生和发展。神经酰胺参与调节细胞周期停滞、细胞凋亡和细胞衰老，并在这些过程中充当细胞内的第二信使。我们先前的研究表明，人血浆神经酰胺浓度与与动脉粥样硬化相关的血脂标志物呈显着正相关。在本研究中，为了揭示氧化应激与动物神经酰胺代谢的关系，我们研究了CCl4引起的氧化应激不仅引起肝脏神经酰胺代谢的变化，而且还引起了肾脏等其他器官神经酰胺代谢的变化。用电喷雾串联质谱仪(LC-MS/MS)分析组织神经酰胺水平。接下来，我们研究了服用链脲佐菌素是否会改变受损组织中的神经酰胺代谢，以及神经酰胺堆积是否与糖尿病引起的并发症的发病机制有关。尽管对照组和糖尿病大鼠的肝脏神经酰胺水平没有差异，但给予链脲佐菌素后，血浆和肾脏神经酰胺水平显著升高。在给药过程中，神经鞘磷脂水解酶的激活导致神经酰胺的增加。因此，我们的数据支持这样的观点，即通过氧化应激过度积累神经酰胺可能在动脉粥样硬化的发病机制中发挥重要作用。

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.