Multicenter Preclinical Validation of BET Inhibition for the Treatment of Pulmonary Arterial Hypertension

• DOI: 10.1164/rccm.201812-2275oc
• Publication Date: 2019-05-01T19:36:22Z
• Authors: Diederik E. Van d...; Kondababu Kurakula; Eve Tremblay; Olivier Boucherat; Guido P. L. Bossers; Robert Szulcek; Alice Bourgeois; Marie-Claude Lampron; Karima Habbout; Sandra Martineau; Roxane Paulin; Ewelina Kulikowski; Ravi Jahagirdar; Ingrid Schalij; Harm Jan Bogaard; Beatrijs Bartelds; Steeve Provencher; Rolf M. F. Berger; Sébastien Bonnet; Marie-José Goumans
• Keywords: BET inhibitor; Pulmonary artery banding; Hypoxia

Rationale: Pulmonary arterial hypertension (PAH) is a degenerative arteriopathy that leads to right ventricular (RV) failure. BRD4 (bromodomain-containing protein 4), member of the BET (bromodomain and extra-terminal motif) family, has been identified as critical epigenetic driver for cardiovascular diseases.Objectives: To explore therapeutic potential in PAH RVX208, clinically available inhibitor.Methods: Microvascular endothelial cells, smooth muscle cells isolated from distal pulmonary arteries patients with PAH, rats Sugen5416 + hypoxia- or monocrotaline shunt-induced RV pressure overload induced by artery banding were treated RVX208 three independent laboratories.Measurements Main Results: upregulated remodeled vasculature where it regulates FoxM1 PLK1, proteins implicated DNA damage response. normalized hyperproliferative, apoptosis-resistant, inflammatory phenotype microvascular PAH. Oral treatment reversed vascular remodeling improved hemodynamics two trials hypoxia-PAH shunt-PAH. could be combined safely contemporary standard care. also supported pressure-loaded rats.Conclusions: inhibitor, modulates proproliferative, prosurvival, proinflammatory pathways, potentially through interactions PLK1. This vitro, diverse rat models. vivo. Together, these data support establishment clinical trial