UCLA

Spontaneous coronary artery dissection (SCAD) and coronary artery disease (CAD) both represent cardiovascular diseases that may result in myocardial infarction and sudden death. However, the populations predominantly impacted by SCAD and CAD as well as the pathogenesis of both diseases are notably different; while SCAD overwhelmingly affects a young, female population and is non-atherosclerotic, CAD mainly impacts males and develops via atherosclerosis. The genetic architecture and mechanisms leading to SCAD onset are currently poorly understood, and although the genetic and environmental risk factors for CAD are better elucidated, further understanding of the mechanisms in which genetic and environmental factors interact to facilitate pathogenesis is needed. We conducted two studies to examine the networks of SCAD and CAD at various omics layers. In a comprehensive multiomics human SCAD study, we investigated disease-associated biological mechanisms and modeled tissue-specific gene regulatory and protein-protein interaction networks across genetic, transcriptomic, and proteomic levels and predicted potential therapeutics for SCAD treatment. We identified various pathways related to the extracellular matrix, immune function, and blood clotting activation. We pinpointed key regulatory genes and hub proteins central within our tissue-specific networks, including HOXB9, CADM1, and COL18A1. Female-specific drugs, such as medroxyprogesterone and progesterone receptor agonist, were prioritized in SCAD drug repositioning. In a single-cell RNA-sequencing mouse study, we examined the cell type-specific transcriptome changes of the aorta in Ldlr-/- mice, an established atherosclerosis animal model for CAD, under various diet conditions, namely chow, high-cholesterol, and high-cholesterol with added trimethylamine N-oxide (TMAO). We identified significant differences in cellular composition in the modulated smooth muscle cell (SMC) cluster and macrophage M1 subtype and elucidated the transition of SMCs into a protective fibromyocyte phenotype in a data-driven manner. Additionally, we determined cell type-specific and shared differentially expressed genes and their corresponding biological pathways across dietary conditions, pinpointing extracellular structure organization pathways as significant in various cell types between high-cholesterol and chow diets as well as apoptosis-related pathways as enriched in SMC and modulated SMC with the addition of TMAO to the high-cholesterol diet. We further predicted intercellular communications that influence downstream gene expression in modulated SMC and endothelial cells.