Pulmonary arterial hypertension (PAH) is a degenerative arteriopathy that leads to right ventricular (RV) failure. BMPR2 loss and DNA damage are early phenomena in its pathogenesis that appear to act in a vicious cycle, driving vascular remodelling via proliferation, inflammation and a shift from a pro-apoptotic to apoptosis-resistant phenotype. Bromodomain-containing protein4 (BRD4) was identified as an epigenetic switch for these processes in response to DNA damage and has a critical role in vascular disease. In preclinical models, BRD4 inhibition by JQ1 and siRNA was shown to improve vascular remodeling and cardiac function, supporting therapeutic benefit in PAH. However, neither JQ1 nor siRNA can be used clinically. We therefore explored the therapeutic potential of RVX208, a clinically available BRD4 antagonist.
Methods and Results.
In two independent laboratories (Canada/the Netherlands), we confirmed that BRD4 is increased in human PAH endothelial and smooth muscle cells and is induced upon genotoxic and pro-inflammatory stress. In both cell types, RVX208 dose-dependently decreased the expression of FoxM1 and PLK1: two oncogenes implicated in the DNA damage response and cell survival. This was associated with reduced proliferation and apoptosis-resistance. Similarly, RVX208 repressed genotoxicity by normalizing the pro-inflammatory phenotype (NFAT/NFκB/TGFβ activity) and by promoting BMPR2/ID1 expression. Oral treatment with RVX208 improved vascular remodeling and pulmonary hemodynamics in both MCT/Shunt and Su5416/Hypoxia rats, and could be combined safely with current PAH therapy (macitentan/tadalafil). As in vitro, these effects were associated with a decrease in vascular FOXM1/PLK1, apoptosis-resistance, inflammation and fibrosis. Finally, RVX208 treatment improved RV contractility in rats with established RV dysfunction induced by pulmonary artery banding.
We report that RVX208, 1) decreases vascular remodeling and inflammation in two PAH rat models, 2) can be combined safely with current PAH therapy and 3) supports the pressure-loaded RV. Together, these findings support the establishment of a clinical trial.