Session 1247 - Interventional Cardiology: Cutting-Edge Translational and Pre-Clinical Research

Poster Session  Sunday March 11, 2018, 3:45 PM - 4:30 PM

1247-298 / 298 - Apabetalone (RVX-208) Modulates Epigenetic Processes in Monocytes and Endothelial Cells Affected by Diabetes Mellitus and Diet That Enhance Risk of Cardiovascular Disease (CVD)

Authors: Christopher Halliday, Laura Tsujikawa, Ewelina Kulikowski, Cyrus Calosing, Sylwia Wasiak, Dean Gilham, Jan Johansson, Mike Sweeney, Norman Wong, Resverlogix Corp., Calgary, Canada

Abstract

Background: RVX-208 lowers major adverse cardiovascular events (MACE) by 57% in diabetes mellitus (DM) patients from post-hoc analysis of phase 2 underpins an ongoing phase 3 BETonMACE trial. How RVX-208, an inhibitor of acetylated lysine binding to epigenetic readers called bromodomain extra-terminal (BET) proteins, may reduce MACE is explored here. In DM, dysglycemia & poor lifestyle habits leading to hyperglycemia & diet derived trimethyl amine oxide (TMAO) raise CVD risks. Perhaps both factors may affect monocyte & endothelial function as reflected in monocyte line (THP-1) & endothelial (HUVEC) cells while RVX-208 attenuates these actions.

Methods: Cultured THP-1, HUVEC & primary human hepatocytes (PHH) cells were exposed to high glucose & TMAO.

Results: In high glucose (25 mM), adhesion of THP-1 to HUVEC cells was enhanced >60-fold but 20 uM RVX-208 blocked this process by 70%. High glucose induced Very Late Antigen-4 (VLA-4) mRNA, a gene mediating THP-1 adhesion 1.3-fold & RVX-208 suppressed it 50%. Similarly in HUVECs RVX-208 abrogated glucose induction by 2- & 1.3-fold of E-selectin & MYD88 mRNA, respectively. Like glucose, 10 uM TMAO enhanced THP-1 adherence to HUVEC cells by 70-fold and RVX-208 lowered this by 70%. RVX-208 also blocked TMAO induction of VLA-4 mRNA by 50% in THP-1. TMAO induction of E-selectin & MYD88 mRNA in HUVEC cells were both lowered by >50% in presence of RVX-208. Dietary phospholipids acted upon by the microbiome & then hepatic flavin mono-oxygenase-3 (FMO3) leads to TMAO. In PHH, 24 hrs exposure to RVX-208 suppresses FMO3 mRNA & protein by 40 & 30%, respectively.

Conclusion: Adhesion of monocyte to endothelium as reflected in the THP-1/HUVEC studies is significantly enhanced by hyperglycemia & TMAO. This pathologic step in CVD is markedly reduced by BET inhibition (BETi) with RVX-208. In support of this finding, BETi lowered expression of genes involved in cellular adhesion; VLA-4 in THP-1 & both E-selectin plus MYD88 in HUVEC cells. Additionally, BETi suppresses hepatocyte mRNA for FMO3 to lower TMAO production. Apabetalone blocks hyperglycemia & TMAO enhanced adhesion of monocytes to endothelial cells & thereby attenuates a pathologic step in CVD to lower MACE.