DOI: 10.1161/circ.148.suppl_1.12881 ISSN: 0009-7322

Abstract 12881: Lnc(RNA)-ing COX-2 and Cardioprotection: A PACERR Story

Elizabeth J Hennessy, Garret A Fitzgerald
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

NSAIDs are amongst the most commonly used drugs by adults, but their use is complicated by an increased risk of adverse cardiovascular events that are consequent to suppression of cyclooxygenase-2 (COX-2) dependent prostaglandin (PG) formation, particularly prostacyclin (PGI 2 ). Amongst the mechanisms HDL may help to mediate cardiovascular risk is via its regulated expression of COX-2 and production of PGI 2 by vascular cells. This affords restraint on thrombogenesis, atherogenesis and hypertension. Another might be to accelerate cholesterol efflux by macrophages in the atherosclerotic plaque. Depletion of COX-2 has been reported to reduce efflux coincident with an altered HDL phenotype that fosters atherogenesis. Long non-coding RNAs (lncRNAs) contribute to the regulation of essential cellular processes, such as the progression of cardiovascular disease. Through the investigation of lncRNAs involved in the cellular response to HDL we have uncovered a regulatory role for a lncRNA encoded on the opposite strand of COX-2, called PACERR. Examining the human GTEx database, we found PACERR is most highly expressed in vascular tissues including aorta with several cis -eQTLs modulating aortic PACERR expression. Patients in the Penn Medicine Biobank with these SNPs exhibit an increase in odds ratio towards vascular inflammatory traits including polyarteritis nodosa (PAN). HDL induces the expression of PACERR in vascular cells, signifying its potential role in mitigating risk towards cardiovascular disease phenotypes. Using gain-and-loss of function approaches we have found that PACERR modulates HDL induced COX-2 and prostaglandin formation by smooth muscle and endothelial cells under flow as well as HDL mediated cholesterol efflux by macrophages via the regulation of the cholesterol transporter ABCG1. By modulating the expression of PACERR in vitro and in vivo, we have elucidated a mechanism by which both HDL and COX-2 have a linked cardio-protective effect contributing to our understanding of the heterogeneous effects of current drugs used to raise HDL cholesterol levels and the cardiotoxicity of NSAIDs observed in clinical trials.

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