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

• Published in: American journal of respiratory and critical care medicine Vol. 200; no. 7; pp. 910 - 920
• Main Authors: Van der Feen, Diederik E, Kurakula, Kondababu, Tremblay, Eve, Boucherat, Olivier, Bossers, Guido P L, Szulcek, Robert, Bourgeois, Alice, Lampron, Marie-Claude, Habbout, Karima, Martineau, Sandra, Paulin, Roxane, Kulikowski, Ewelina, Jahagirdar, Ravi, Schalij, Ingrid, Bogaard, Harm Jan, Bartelds, Beatrijs, Provencher, Steeve, Berger, Rolf M F, Bonnet, Sébastien, Goumans, Marie-José
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01-10-2019
• Subjects: Animals; Apoptosis - drug effects; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Proliferation - drug effects; Cells; Chronic obstructive pulmonary disease; Disease Models, Animal; DNA Repair; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Forkhead Box Protein M1 - genetics; Gene Expression Regulation; Humans; Inflammation; Microvessels - metabolism; Muscle, Smooth, Vascular - metabolism; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Polo-Like Kinase 1; Polycyclic aromatic hydrocarbons; Protein Serine-Threonine Kinases - genetics; Proto-Oncogene Proteins - genetics; Pulmonary Arterial Hypertension - genetics; Pulmonary Arterial Hypertension - metabolism; Pulmonary Artery - cytology; Pulmonary Artery - metabolism; Pulmonary hypertension; Quinazolinones - pharmacology; Rats; Recreational vehicles; Transcription Factors - antagonists & inhibitors; Transcription Factors - metabolism; Vascular Remodeling - drug effects; BRD4 (bromodomain-containing protein 4); right ventricle pressure load; vascular remodeling; pulmonary arterial hypertension; BET inhibition
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.201812-2275OC

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.
To explore the therapeutic potential in PAH of RVX208, a clinically available BET inhibitor.
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.
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.
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
, and in diverse PAH rat models. RVX208 also supported the pressure-loaded RV
. Together, these data support the establishment of a clinical trial with RVX208 in patients with PAH.