BET Signaling: A Novel Therapeutic Target for Pulmonary Hypertension?

To the Editor:

Pulmonary hypertension (PH) is a progressive clinical condition with poor prognosis if the patients do not receive adequate therapy. Recent clinical trials demonstrate that combined therapy with multiple drugs improves pulmonary arterial hypertension outcomes more significantly compared with monotherapy (1, 2). However, there are only three types of drugs targeting PH, including the nitric oxide–cyclic guanosine monophosphate pathway, prostacyclin pathway, and endothelin pathway, in current clinical practice. Thus, introduction of new drugs targeting novel pathways may provide more combination options, especially for patients with pulmonary arterial hypertension who are resistant to or show adverse effects from current drugs. In a recent issue of the Journal, Van der Feen and colleagues (3) report that a clinically available BET (bromodomain and extraterminal motif) inhibitor, RVX-208, shows therapeutic effects on three preclinical PH models, with reduced pulmonary vascular resistance, increased cardiac output, and decreased pulmonary vascular remodeling and inflammation through FoxM1 (forkhead box protein M1) and PLK1 (polo-like kinase) signaling pathways. In cultured cells from patients with PH, RVX-208 suppresses pulmonary artery smooth muscle cell proliferation and endothelial cell inflammation through FoxM1/PLK1 pathways also. Drugs targeting these novel pathways have not been used for patients with PH yet because RVX-208 is now clinically available only for coronary artery disease. The promising in vivo and in vitro data from Van der Feen and colleagues suggest that RVX-208 may bring new hope for patients with PH. It is of note that RVX-208 shows synergistic effects with current PH-target drugs such as tadalafil and macitentan in PH models, which is extremely important because combination therapy has been recommended for patients with PH according to recent guidelines for PH practice.

However, there are some pitfalls of this study; most of the PH-target drugs have the side effect of dilating blood vessels in systemic circulation. Given the fact that most patients with PH have relatively low blood pressure, it is very important to monitor the change of blood pressure after administration of PH-target drugs. In clinical practice, plasma level of BNP (B-type natriuretic peptide) and right atrial pressure are used to assess the severity and predict the prognosis of PH. It would be interesting to know the changes of blood pressure, BNP, and right atrial pressure on the PH animals in this study.