Department of Biochemistry, Faculty of Medicine, Medical University of Gdansk, 1 Debinki St, 80-211, Gdansk, Poland.
Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 14 Bobrzynskiego St., 30-348, Krakow, Poland.
J Transl Med. 2021 Jan 6;19(1):6. doi: 10.1186/s12967-020-02663-8.
Dyslipidaemia is a major risk factor for atherosclerosis and cardiovascular diseases. The molecular mechanisms that translate dyslipidaemia into atherogenesis and reliable markers of its progression are yet to be fully elucidated. To address this issue, we conducted a comprehensive metabolomic and proteomic analysis in an experimental model of dyslipidaemia and in patients with familial hypercholesterolemia (FH).
Liquid chromatography/mass spectrometry (LC/MS) and immunoassays were used to find out blood alterations at metabolite and protein levels in dyslipidaemic ApoE/LDLR mice and in FH patients to evaluate their human relevance.
We identified 15 metabolites (inhibitors and substrates of nitric oxide synthase (NOS), low-molecular-weight antioxidants (glutamine, taurine), homocysteine, methionine, 1-methylnicotinamide, alanine and hydroxyproline) and 9 proteins (C-reactive protein, proprotein convertase subtilisin/kexin type 9, apolipoprotein C-III, soluble intercellular adhesion molecule-1, angiotensinogen, paraoxonase-1, fetuin-B, vitamin K-dependent protein S and biglycan) that differentiated FH patients from healthy controls. Most of these changes were consistently found in dyslipidaemic mice and were further amplified if mice were fed an atherogenic (Western or low-carbohydrate, high-protein) diet.
The alterations highlighted the involvement of an immune-inflammatory response system, oxidative stress, hyper-coagulation and impairment in the vascular function/regenerative capacity in response to dyslipidaemia that may also be directly engaged in development of atherosclerosis. Our study further identified potential biomarkers for an increased risk of atherosclerosis that may aid in clinical diagnosis or in the personalized treatment.
血脂异常是动脉粥样硬化和心血管疾病的主要危险因素。将血脂异常转化为动脉粥样硬化的分子机制以及其进展的可靠标志物尚未完全阐明。为了解决这个问题，我们在血脂异常的实验模型和家族性高胆固醇血症（FH）患者中进行了全面的代谢组学和蛋白质组学分析。
采用液相色谱/质谱（LC/MS）和免疫测定法，在血脂异常 ApoE/LDLR 小鼠和 FH 患者中寻找代谢物和蛋白质水平的血液变化，以评估其与人类的相关性。
我们鉴定出 15 种代谢物（一氧化氮合酶（NOS）的抑制剂和底物、低分子量抗氧化剂（谷氨酰胺、牛磺酸）、同型半胱氨酸、蛋氨酸、1-甲基烟酰胺、丙氨酸和羟脯氨酸）和 9 种蛋白质（C 反应蛋白、脯氨酸内切酶/subtilisin/kexin 9 型、载脂蛋白 C-III、可溶性细胞间黏附分子-1、血管紧张素原、对氧磷酶-1、胎球蛋白-B、维生素 K 依赖性蛋白 S 和 biglycan），可将 FH 患者与健康对照者区分开来。这些变化在血脂异常的小鼠中得到了一致的发现，如果给小鼠喂食致动脉粥样硬化的（西方或低碳水化合物、高蛋白）饮食，这些变化会进一步放大。
这些变化突出了免疫炎症反应系统、氧化应激、高凝和血管功能/再生能力受损的参与，这些变化可能也直接参与了动脉粥样硬化的发生。我们的研究进一步确定了动脉粥样硬化风险增加的潜在生物标志物，这些标志物可能有助于临床诊断或个体化治疗。
