Thrombosis and Atherosclerosis Research Institute, McMaster University, 237 Barton Street East, Hamilton, ON, L8L 2X2, Canada.
Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON, Canada.
Metabolomics. 2018 Jul 3;14(7):92. doi: 10.1007/s11306-018-1392-2.
Three out of four people with diabetes will die of cardiovascular disease. However, the molecular mechanisms by which hyperglycemia promotes atherosclerosis, the major underlying cause of cardiovascular disease, are not clear.
Three distinct models of hyperglycemia-associated accelerated atherosclerosis were used to identify commonly altered metabolites and pathways associated with the disease.
Normoglycemic apolipoprotein-E-deficient mice served as atherosclerotic control. Hyperglycemia was induced by multiple low-dose streptozotocin injections, or by introducing a point-mutation in one copy of insulin-2 gene. Glucosamine-supplemented mice, which experience accelerated atherosclerosis to a similar extent as hyperglycemia-induced models without alterations in glucose or insulin levels, were also included in the analysis. Untargeted plasma metabolomics were used to investigate hyperglycemia-associated accelerated atherosclerosis in three disease models. The effect of specific significantly altered metabolites on pro-atherogenic processes was investigated in cultured human vascular cells.
Hyperglycemic and glucosamine-supplemented mice showed distinct metabolomic profiles compared to controls. Meta-analysis of three disease models revealed 62 similarly altered metabolite features (FDR-adjusted p < 0.05). Identification of shared metabolites revealed alterations in glycerophospholipid and sphingolipid metabolism, and pro-atherogenic processes including inflammation and oxidative stress. Post-multivariate and pathway analyses indicated that the glycosphingolipid pathway is strongly associated with hyperglycemia-induced accelerated atherosclerosis in these atherogenic mouse models. Glycosphingolipids induced oxidative stress and inflammation in cultured human vascular cells.
Glycosphingolipids are strongly associated with hyperglycemia-induced accelerated atherosclerosis in three distinct models. They also promote pro-atherogenic processes in cultured human cells. These results suggest glycosphingolipid pathway may be a potential therapeutic target to block or slow atherogenesis in diabetic patients.
四分之三的糖尿病患者会死于心血管疾病。然而，高血糖促进动脉粥样硬化（心血管疾病的主要潜在原因）的分子机制尚不清楚。
使用三种不同的高血糖相关加速动脉粥样硬化模型，确定与该疾病相关的常见改变代谢物和途径。
正常血糖载脂蛋白-E 缺陷小鼠作为动脉粥样硬化对照。通过多次小剂量链脲佐菌素注射或引入胰岛素-2 基因一个拷贝的点突变来诱导高血糖。还包括补充葡糖胺的小鼠，其经历与高血糖诱导模型相似程度的加速动脉粥样硬化，但葡萄糖或胰岛素水平没有改变，也包括在分析中。使用非靶向血浆代谢组学研究三种疾病模型中的高血糖相关加速动脉粥样硬化。在培养的人血管细胞中研究特定显著改变的代谢物对促动脉粥样硬化过程的影响。
高血糖和葡糖胺补充小鼠与对照相比表现出明显不同的代谢组学特征。对三种疾病模型的荟萃分析显示有 62 个相似改变的代谢物特征（FDR 调整后的 p < 0.05）。共享代谢物的鉴定显示甘油磷脂和鞘脂代谢以及促动脉粥样硬化过程（包括炎症和氧化应激）的改变。多元和途径后分析表明，糖鞘脂途径与这些致动脉粥样硬化小鼠模型中的高血糖诱导的加速动脉粥样硬化密切相关。糖鞘脂在培养的人血管细胞中诱导氧化应激和炎症。
糖鞘脂与三种不同模型中的高血糖诱导加速动脉粥样硬化密切相关。它们还促进培养的人细胞中的促动脉粥样硬化过程。这些结果表明糖鞘脂途径可能是阻止或减缓糖尿病患者动脉粥样硬化形成的潜在治疗靶点。
