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Analysis of urinary exosomal metabolites identifies cardiovascular risk signatures with added value to urine analysis
BMC Biology ( IF 5.4 ) Pub Date : 2020-12-14 , DOI: 10.1186/s12915-020-00924-y
Marta Agudiez 1 , Paula J Martinez 1 , Marta Martin-Lorenzo 1 , Angeles Heredero 2 , Aranzazu Santiago-Hernandez 1 , Dolores Molero 3 , Juan Manuel Garcia-Segura 3, 4 , Gonzalo Aldamiz-Echevarria 2 , Gloria Alvarez-Llamas 1, 5
Affiliation  

Subclinical atherosclerosis may result in fatal cardiovascular (CV) events, but the underlying mechanisms and molecular players leading to disease are not entirely understood. Thus, novel approaches capable of identifying the factors involved in pathological progression and providing a better understanding of the subjacent mechanisms are needed. Extracellular vesicles (EVs) have been shown to have numerous biological functions, and their metabolome has recently generated interest as a source of novel biomarkers. The metabolic content of the exosomes has been so far unexplored in cardiovascular disease (CVD), and here, we developed an analytical strategy aimed at probing urinary exosomal metabolite content and its association to CV risk. Direct analysis of the exosomes without metabolite extraction was evaluated by high-resolution magic angle spinning (1H HR-MAS). Other two methodologies for the analysis of exosomal metabolites by 1H NMR were set up, based on methanol or organic solvents sequential extraction. The three methods were compared in terms of the number of detected signals and signal to noise ratio (S/N). The methanol method was applied to identify altered metabolites in the urinary exosomes of subjects with programmed coronary artery by-pass grafting (CABG) versus a control group. Target mass spectrometry (MS) was also performed for differential analysis. The clinical performance of exosomal metabolites of interest in CVD was investigated, and the added value of the exosomes compared to urine analysis was evaluated. Based on S/N ratio, simplicity, reproducibility, and quality of the spectrum, the methanol method was chosen for the study in CVD. A cardiometabolic signature composed by 4-aminohippuric acid, N-1-methylnicotinamide, and citric acid was identified in urinary exosomes. Directly in urine, 4-aminohippuric acid and citric acid do not show variation between groups and changes in N-1-methylnicotinamide are less pronounced, proving the added value of exosomes. We set up a novel methodology to analyze metabolic alterations in urinary exosomes and identified a cardiometabolic signature in these microvesicles. This study constitutes the first evidence of a role for the exosomal metabolism in CVD and demonstrates the possibility to evaluate the urinary exosomal metabolic content by NMR and MS.

中文翻译:

尿液外泌体代谢产物分析可确定心血管风险特征,为尿液分析增值

亚临床性动脉粥样硬化可能导致致命的心血管(CV)事件,但是导致疾病的潜在机制和分子因素尚不完全清楚。因此,需要能够识别与病理进展有关的因素并更好地理解其下层机制的新颖方法。细胞外囊泡(EVs)已被证明具有多种生物学功能,它们的代谢组最近引起了人们的兴趣,作为新型生物标志物的来源。迄今为止,外泌体的代谢含量尚未在心血管疾病(CVD)中得到开发,在这里,我们开发了一种分析策略,旨在探查尿中外泌体代谢产物的含量及其与CV风险的关系。通过高分辨率魔角旋转(1H HR-MAS)评估了没有代谢物提取的外泌体的直接分析。建立了另外两种通过1H NMR分析外泌体代谢物的方法,基于甲醇或有机溶剂顺序萃取。根据检测到的信号数量和信噪比(S / N)比较了这三种方法。与对照组相比,采用甲醇法确定了冠状动脉旁路移植术(CABG)受试者尿外泌体中代谢产物的变化。还进行了目标质谱(MS)进行差异分析。研究了在CVD中关注的外泌体代谢物的临床表现,并评估了与尿液分析相比的外泌体附加值。基于信噪比,简单性,可重复性,在光谱质量方面,选择了甲醇法进行CVD研究。在尿液外泌体中发现了由4-氨基马尿酸,N-1-甲基烟酰胺和柠檬酸组成的心脏代谢特征。直接在尿液中,4-氨基马尿酸和柠檬酸在组之间没有显示变化,并且N-1-甲基烟酰胺的变化不太明显,证明了外泌体的附加值。我们建立了一种新颖的方法来分析尿外泌体的代谢变化,并在这些微囊泡中确定了心脏代谢的特征。这项研究构成了外泌体代谢在CVD中的作用的第一个证据,并证明了通过NMR和MS评估尿液外泌体代谢含量的可能性。在尿液外泌体中发现了由4-氨基马尿酸,N-1-甲基烟酰胺和柠檬酸组成的心脏代谢特征。直接在尿液中,4-氨基马尿酸和柠檬酸在组之间没有显示变化,并且N-1-甲基烟酰胺的变化不太明显,证明了外泌体的附加值。我们建立了一种新颖的方法来分析尿外泌体的代谢变化,并在这些微囊泡中确定了心脏代谢的特征。这项研究构成了外泌体代谢在CVD中的作用的第一个证据,并证明了通过NMR和MS评估尿液外泌体代谢含量的可能性。在尿液外泌体中鉴定出由4-氨基马尿酸,N-1-甲基烟酰胺和柠檬酸组成的心脏代谢特征。直接在尿液中,4-氨基马尿酸和柠檬酸在组之间没有显示变化,并且N-1-甲基烟酰胺的变化不太明显,证明了外泌体的附加值。我们建立了一种新颖的方法来分析尿外泌体的代谢变化,并在这些微囊泡中确定了心脏代谢的特征。这项研究构成了外泌体代谢在CVD中的作用的第一个证据,并证明了通过NMR和MS评估尿液外泌体代谢含量的可能性。4-氨基马尿酸和柠檬酸没有显示组之间的变化,并且N-1-甲基烟酰胺的变化不太明显,证明了外泌体的附加值。我们建立了一种新颖的方法来分析尿外泌体的代谢变化,并在这些微囊泡中确定了心脏代谢的特征。这项研究构成了外泌体代谢在CVD中的作用的第一个证据,并证明了通过NMR和MS评估尿液外泌体代谢含量的可能性。4-氨基马尿酸和柠檬酸没有显示组间的变化,并且N-1-甲基烟酰胺的变化不太明显,证明了外泌体的附加值。我们建立了一种新颖的方法来分析尿外泌体的代谢变化,并在这些微囊泡中确定了心脏代谢的特征。这项研究构成了外泌体代谢在CVD中的作用的第一个证据,并证明了通过NMR和MS评估尿液外泌体代谢含量的可能性。
更新日期:2020-12-14
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