S38 The Brd4 Inhibitor, Jq1 Decreases Proliferation And Arrests The Cell Cycle Of Pulmonary Vascular Cells: Implications For Pulmonary Arterial Hypertension

Abstract

Background Pulmonary arterial hypertension (PAH) is an incurable disease characterised by raised pulmonary resistance, resulting from vascular remodelling which leads to right heart failure and death. Recently NF-kB mediated inflammatory gene expression and vascular proliferation/remodelling have been shown to be involved in the pathogenesis of PAH. The expression of subsets of NF-kB-induced inflammatory genes is dependent upon the recruitment of the bromodomains and extra-terminal (BET) family of proteins to the transcriptional activation complex. We hypothesise that inhibition of BET proteins which bind acetylated lysine residues on histones and non-histone proteins will attenuate the hyperproliferative and proinflammatory phenotype of vascular cells. Methods Primary human pulmonary vascular endothelial cells (P-EC) were serum starved for 24 h prior to treatment with the Brd4 mimic JQ1+ or JQ1- (inactive enantiomer) in complete (5% FCS) media. P-EC cell proliferation was measured by BrdU incorporation and apoptosis was determined using caspase 3/7 activity. Cell cycle progression was determined by FACs analysis. mRNA levels of cell cycle genes and inflammatory cytokines were measured by RT-PCR. MTT assay was used to measure cell viability. Results JQ1+ caused a significant (p Conclusion Inhibition of Brd4 with JQ1 decreases remodelling and inflammation in P-EC via a decrease in proliferation, cell cycle arrest and an increase in apoptosis. Further work is required but Brd4 inhibition may provide therapeutic drugs for the treatment of PAH.