Identification of Inflammatory Factors Contributing to Foaming in Atherosclerosis

According to the National Institute of Health (NIH), atherosclerosis is attributed to the majority of cardiovascular disease (CVD) cases and is the leading cause of mortality in the US and worldwide. Despite significant medical advancements, the risk of cardiovascular events remains, warranting further mechanistic and pathogenic investigation. Advances in high-resolution omics profiling and the development of novel data-analytic bioinformatic tools previously enabled the novel discovery of two distinct programs in foaming, the central process in atherogenesis. The programs are pathogenic and homeostatic foaming, with the pathogenic foaming program being positively associated with disease. Using single-cell RNA sequencing (scRNA-seq) data from mouse aorta, transcription factors IRF7, ELL2, ARID3A, and MGA were identified as drivers of pathogenic foaming in atherosclerosis. Causal network analysis further revealed eight upstream regulators of these drivers. Expression analysis in symptomatic and asymptomatic sequencing data from independent human and mouse datasets confirmed the significance of these 12 genes/complexes/channels/receptors. The results of this study provide specific causal regulators for the pathogenesis of atherosclerosis and potentially offer new targetable molecules and their downstream network for novel therapeutic designs that direct treatments toward targeting inflammation.