Abstract
Atherosclerosis can occur throughout the arterial vascular system and lead to various diseases. Early diagnosis of atherosclerotic processes and of individual disease patterns would be more likely to be successful if targeted therapies were available. For this, it is important to find reliable biomarkers that are easily accessible and with little inconvenience for patients. There are many cell culture, animal model or tissue studies that found biomarkers at the microRNA (miRNA) and mRNA level describing atherosclerotic processes. However, little is known about their potential as circulating and liquid biopsy markers in patients. In this study, we examined serum-derived miRNA – profiles from 129 patients and 28 volunteers to identify potential biomarkers. The patients had four different atherosclerotic manifestations: abdominal aneurysm (n = 35), coronary heart disease (n = 34), carotid artery stenosis (n = 24) and peripheral arterial disease (n = 36). The samples were processed with an extracellular vesicle enrichment protocol, total-RNA extraction and small RNA-sequencing were performed. A differential expression analysis was performed bioinformatically to find potentially regulated miRNA biomarkers. Resulting miRNA candidates served as a starting point for an overrepresentation analysis in which relevant target mRNAs were identified. The Gene Ontology database revealed relevant biological functions in relation to atherosclerotic processes. In patients, expression of specific miRNAs changed significantly compared to healthy volunteers; 27 differentially expressed miRNAs were identified. We were able to detect a group-specific miRNA fingerprint: miR-122-5p, miR-2110 and miR-483-5p for abdominal aortic aneurysm, miR-370-3p and miR-409-3p for coronary heart disease, miR-335-3p, miR-381-3p, miR493-5p and miR654-3p for carotid artery stenosis, miR-199a-5p, miR-215-5p, miR-3168, miR-582-3p and miR-769-5p for peripheral arterial disease. The results of the study show that some of the identified miRNAs have already been associated with atherosclerosis in previous studies. Overrepresentation analysis on this data detected biological processes that are clearly relevant for atherosclerosis, its development and progression showing the potential of these miRNAs as biomarker candidates. In a next step, the relevance of these findings on the mRNA level is to be investigated and substantiated.
Highlights
Atherosclerosis is a chronic arterial disease and a leading cause of vascular death worldwide
The aim of this study was on the one hand to identify circulating miRNAs that can serve as biomarker candidates for atherosclerosis; on the other hand, to investigate whether a subgroup unique miRNA-profile can be determined for the four different atherosclerotic manifestations
Patients were identified after the attending physician made the diagnosis of atherosclerotic disease and categorized the patients according to the presence of the following manifestations of the disorder: 34 patients had coronary heart disease, 36 patients had peripheral artery disease, 24 patients had carotid stenosis, 35 patients had abdominal aortic aneurysm severe enough to require surgical intervention
Summary
Atherosclerosis is a chronic arterial disease and a leading cause of vascular death worldwide. The vascular mortality risk has declined substantially over the last decades from 16% in 1980 to 4% in 2010 in high income countries, some countries (in particular Eastern Europe and parts of Asia) still report increases in mortality rates (Bennett et al, 2014; Moran et al, 2014) Despite these trends, atherosclerosis remains the leading cause of premature adult morbidity and mortality worldwide (GBD 2013 Mortality and Causes of Death Collaborators, 2015). Technological progress in molecular biology is leading to more and more knowledge in the context of circulating biomarkers, e.g., by analyzing extracellular vesicles (EVs) and the connected miRNAs of cardiovascular diseases. This makes EVrelated miRNA biomarkers an interesting subject of investigation (Reithmair et al, 2017)
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