Comprehensive proteomics analysis of plasma from ApoE- and LDLR- deficient mice reveals atherosclerosis biomarkers with potential application in clinic

Cardiovascular diseases originated by atherosclerosis are the main cause of death worldwide. The objective of this work is to study the mechanisms underlying atherosclerosis based on two atherosclerotic mouse models, as well as to find disease biomarkers with potential application in the clinical setting.

A proteomics analysis has been carried out on two mouse models, ApoE KO (apolipoprotein E knockout) and LDLR KO (low-density lipoprotein receptor knockout), which were fed with different diets. Plasma protein digestion was followed by multiplexed stable isotope labelling of peptides, protein identification and protein function analysis.

Results highlight that in both clinical atherosclerotic models functional categories such as lipid metabolism, complement system, immunoglobulin regulation, blood coagulation and extracellular matrix remodeling are altered. Comparison of the corresponding protein components between the two mouse models showed marked differences regarding complement activation components and blood coagulation regulators. ApoE KO model was further analyzed to assess differences between the clinical and the subclinical model and the effect of gut microbiota. This analysis revealed eight potential biomarkers to discriminate between clinical and subclinical atherosclerotic stages and seven pointer proteins that could understand the molecular mechanisms undergoing the impact of the gut microbiota metabolism on the atherosclerosis.

Finally, this proteomics study has been compared with three human cohorts: individuals with clinical (carotid wall lesions, n=48) and subclinical (PESA (n=444) and AWHS (n=350) studies) atherosclerosis. It was observed that the ApoE KO plasma proteomic profile resembles more closely its human counterpart as compared to the LDLR KO model. Moreover, a link has been established between gut microbiota and atherosclerosis, and potential biomarkers have been proposed.