Abstract 14313: A Proteomic Atlas of Human Coronary Artery Reveals the Pathological Progression of Atherosclerosis

Abstract

Introduction: The key molecular mechanisms associated with human atherosclerotic plaque progression, atherosclerotic lesion initiation and plaque destabilization are not fully understood. Hypothesis: Different stages of atherosclerosis (AS) progression have distinct pathological processes. Some key proteins induce AS progression. Methods: We employed 20 coronary artery samples among 4 explanted hearts from coronary heart disease patients. Each heart contains stages of unaffected control (NC), pathological intimal thickening (PIT), fibroatheroma (FA), transition to thin-cap fibroatheroma (TCFA) and ruptured plaque (RP), which were validated by hematoxylin and eosin (H&E) staining. We performed quantitative proteomics in each of the samples based on tandem-mass-tags and liquid chromatography-tandem mass spectrometry. Furthermore, we measured proteins in human coronary artery tissue via immunofluorescence. Results: Proteomics revealed that extracellular matrix (ECM) organization was the most significantly enriched pathway in PIT. FA exhibited an enrichment of immunologic processes, such as neutrophil degranulation, myeloid leukocyte activation and innate immune response. Molecular profiles of TCFA and RP are similar, with complement and coagulation cascades pathway as a hallmark of these stages. Clustering analysis of DEPs displayed 4 clusters, notably cluster 2 had a precipitous elevation from FA to TCFA. Within this cluster, we identified a high-rank molecule: macrophage-capping protein (CAPG). Immunohistochemistry and immunofluorescence revealed that CAPG is highly elevated in plaque compared to NC and is specifically expressed in the plaque. Conclusions: ECM organization was continuously dysregulated in AS progression. Immune response might initiate the atherosclerotic plaque. Complement and coagulation cascades pathway was a hallmark of TCFA and RP. CAPG might be a therapeutic target for AS progression.