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

氧化应激与动脉粥样硬化的发生和发展有关。神经酰胺参与调控细胞周期阻滞、细胞凋亡和细胞衰老，并在这些过程中作为细胞内第二信使。我们之前的研究表明，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显著正相关。为了揭示动物氧化应激与神经酰胺代谢的关系，我们研究了氧化应激通过给药CCl_4诱导神经酰胺代谢的变化，不仅在肝脏，而且在其他器官如肾脏。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并发症的发病机制有关。虽然在对照组和糖尿病大鼠之间没有观察到肝神经酰胺水平的差异，但STZ给药后血浆和肾神经酰胺水平显著升高。经STZ处理后，可将鞘磷脂水解为神经酰胺的鞘磷脂酶的激活可导致血浆中神经酰胺的增加。因此，我们的数据支持了神经酰胺通过氧化应激的过度积累可能在动脉粥样硬化发病机制中起重要作用的观点。

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.