Background

The proteome of human coronary arteries can be considered as a complex network with architectural features that vary considerably depending on the presence or absence of coronary artery atherosclerosis. The characterization of these molecular proteomic signatures in healthy and atherosclerotically altered human coronary arteries, as well as their biological significance, remains largely unexplored.

Aims

We wish to 1) provide a proteomic atlas of phenotypically healthy and atherosclerotically altered coronary arteries, 2) compare the proteomic signatures between individuals suffering from CAD and healthy controls and 3) highlight potential biomarkers and pathways that might improve CAD risk prediction and assessment of plaque stability in the future.

Methods

Age- and sex-matched human coronaries from an established postmortem biobank of CAD patients (n=10) and phenotypically healthy controls (n=10) were used for this study. Based on the proximal part of the left anterior descending (LAD), histological evaluation of formalin-fixed and paraffin-embedded (FFPE) specimens was performed after hematoxylin and eosin (H&E) staining according to modified AHA classification. Subsequently, defined areas of media, necrotic core, and fibrous cap and their corresponding areas were excised from histological characterized FFPE vessel samples by laser microdissection and analyzed by high-resolution mass-spectrometer (MS) assisted proteomic analysis. Particular focus was on the protective layer of the atherosclerotic plaque, the fibrous cap.

Results

MS analysis revealed >4.500 different proteins from coronary samples providing a comprehensive proteomic atlas of human coronary arteries in individuals with CAD and healthy controls. Comparing both phenotypes we identified several differentially expressed proteins that might serve as future biomarkers or treatment targets. On pathway level we found significant disturbance of mitochondrial energy metabolism, mitochondrial dysfunction, cholesterol metabolism, epigenetic signaling and various inflammation associated pathways. The necrotic core of unstable plaques contained more proteins related to inflammation, especially NF-κB mediated, compared to media and fibrous cap. Regarding plaque stability, we detected certain proteins exclusively differentially expressed in the fibrous cap of unstable plaques.

Conclusion

We present a comprehensive, novel atlas of the proteomic landscape of human coronary arteries in health and disease. Our resource is of high scientific relevance for the biological understanding of CAD, identification of potential biomarkers, improved risk prediction, and will stimulate targeted therapeutic approaches to reduce the burden of CAD and prevent myocardial infarction in the future.