动脉粥样硬化和由此导致的心血管疾病是美国死亡的主要原因。高同型半胱氨酸血症(HHcy),或中间氨基酸高半胱氨酸的积累,是动脉粥样硬化的独立危险因素,但是介导这种效应的复杂生物过程仍然难以捉摸。几个因素调节同型半胱氨酸水平,包括几种酶的活性和足够水平的辅酶,包括磷酸吡哆醛(维生素B6),叶酸(维生素B9),和甲基钴胺(维生素B12)。为了更好地理解HHcy对动脉粥样硬化发生发展的生物学影响,载脂蛋白E缺陷(apoE-/-小鼠),人类动脉粥样硬化的模型,饲喂高同型半胱氨酸饮食(甲基供体和B族维生素含量低)(HHD)或对照饮食(CD)。八周后,等离子体,主动脉,收集肝脏来定量甲基化代谢物,而血浆也用于广泛靶向代谢组学分析。通过14T磁共振成像(MRI)定量头臂动脉(BCA)中的主动脉斑块负荷。观察到血浆和肝同型半胱氨酸的严重积累和增加的BCA斑块负荷,从而证实了HHD的致动脉粥样硬化作用。此外,血浆和主动脉的甲基化能力下降,通过在HHD小鼠中检测到S-腺苷甲硫氨酸与S-腺苷同型半胱氨酸(SAM:SAH)的比率间接评估,主动脉还子氨酸水平增加了172倍。表明通过转硫途径的通量增加。甜菜碱及其代谢前体,胆碱,与CD小鼠相比,HHD小鼠的肝脏显着降低。检测到HHD小鼠与CD动物的血浆代谢组的广泛变化,包括酰基肉碱的改变,氨基酸,胆汁酸,神经酰胺,鞘磷脂,三酰甘油水平,和功能失调的脂质代谢的几个指标。这项研究证实了严重HHcy在血管斑块进展中的相关性,并提示了新的代谢途径与动脉粥样硬化的病理生理学有关。
Atherosclerosis and resulting cardiovascular disease are the leading causes of death in the US. Hyperhomocysteinemia (HHcy), or the accumulation of the intermediate amino acid homocysteine, is an independent risk factor for atherosclerosis, but the intricate biological processes mediating this effect remain elusive. Several factors regulate homocysteine levels, including the activity of several enzymes and adequate levels of their coenzymes, including pyridoxal phosphate (vitamin B6), folate (vitamin B9), and methylcobalamin (vitamin B12). To better understand the biological influence of HHcy on the development and progression of atherosclerosis, apolipoprotein-E-deficient (apoE-/- mice), a model for human atherosclerosis, were fed a hyperhomocysteinemic diet (low in methyl donors and B vitamins) (HHD) or a control diet (CD). After eight weeks, the plasma, aorta, and liver were collected to quantify methylation metabolites, while plasma was also used for a broad targeted metabolomic analysis. Aortic plaque burden in the brachiocephalic artery (BCA) was quantified via 14T magnetic resonance imaging (MRI). A severe accumulation of plasma and hepatic homocysteine and an increased BCA plaque burden were observed, thus confirming the atherogenic effect of the HHD. Moreover, a decreased methylation capacity in the plasma and aorta, indirectly assessed by the ratio of S-adenosylmethionine to S-adenosylhomocysteine (SAM:SAH) was detected in HHD mice together with a 172-fold increase in aortic cystathionine levels, indicating increased flux through the transsulfuration pathway. Betaine and its metabolic precursor, choline, were significantly decreased in the livers of HHD mice versus CD mice. Widespread changes in the plasma metabolome of HHD mice versus CD animals were detected, including alterations in acylcarnitines, amino acids, bile acids, ceramides, sphingomyelins, triacylglycerol levels, and several indicators of dysfunctional lipid metabolism. This study confirms the relevance of severe HHcy in the progression of vascular plaque and suggests novel metabolic pathways implicated in the pathophysiology of atherosclerosis.