Elizabeth J Hennessy, Takae Tanosaki, Ronan Lordan, Soon Yew Tang, Vladimir V Shuvaev, Soumita Ghosh, Ujjalkumar S Das, Robin Joshi, Hu Meng, John N Snouwaert, Hanna Winter, Lars Maegdefessel, Beverly H Koller, Garret A FitzGerald
Cyclooxygenase-2 (COX-2) plays a central role in inflammation, but its inhibition is associated with increased cardiovascular risk. Here, we investigate the COX-2 antisense long non-coding RNA (lncRNA) PTGS2 antisense complex-mediated expression regulator RNA (PACERR) and its potential role in pathways linking inflammation and cholesterol homeostasis. PACERR expression is induced by high-density lipoprotein (HDL) and lipopolysaccharide (LPS) and is associated with changes in COX-2, ABCA1, and ABCG1 expression in vascular (smooth muscle and endothelial) and immune cells (macrophages). PACERR interacts with regulatory proteins p300, hnRNPL, and IκBζ, and its perturbation alters their association with target loci. Silencing PACERR enhances HDL-induced cholesterol efflux and modifies COX-2 expression and prostaglandin production. PACERR is also associated with regulatory elements near PLA2G4A (cPLA2), and its perturbation influences cPLA2 expression and arachidonic acid release. In inflammatory settings, PACERR silencing reduces COX-2 expression, prostaglandin biosynthesis, and systemic inflammatory responses. Together, these findings support a role for PACERR in coordinating inflammatory and cholesterol-responsive pathways.