Schematic flow of analytic and experimental validation steps.
A. Genes differentially expressed in response to 15
antiretroviral therapy (ART) drugs were identified in the LINCS database. Their
enrichments and co-expression were then sought in 30 regulatory gene networks
(RGNs) identified in the STAGE study as coronary artery disease
(CAD)-causal.22 Genes
most essential for the activity of RGNs, or key drivers (K1-K5) were also
included in this analysis. B. A schematic example of a RGN with 5
key disease drivers. C. Experimental validation of
atherosclerosis-related RGN (AR-RGN) enriched in ART signatures using an
atherosclerosis model in vitro. THP-1 monocytes were
differentiated into THP-1 macrophages in vitro and then
incubated with AcLDL and individual ART drugs to form THP-1 foam cells. To
assess the role of key driver genes in AR-RGN in foam cell formation induced by
ART drugs, THP-1 macrophages were subjected to key driver silencing. CVD,
cardiovascular disease. STAGE, the Stockholm Atherosclerosis Gene Expression
study.22 Red color
exemplifies downregulated genes, green color upregulated genes.