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 inhibition; 0301 basic medicine; DNA Repair; vascular remodeling; Myocytes, Smooth Muscle; Apoptosis; Cell Cycle Proteins; Protein Serine-Threonine Kinases; Pulmonary Artery; Muscle, Smooth, Vascular; BRD4 (bromodomain-containing protein 4); 03 medical and health sciences; INFLAMMATION; pulmonary arterial hypertension; Proto-Oncogene Proteins; Animals; Humans; Cell Proliferation; Quinazolinones; Inflammation; Pulmonary Arterial Hypertension; RECEPTOR; Forkhead Box Protein M1; FOXM1; Endothelial Cells; CANCER; Rats; 3. Good health; Disease Models, Animal; Gene Expression Regulation; Microvessels; right ventricle pressure load; EMC COEUR-09

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