New perspectives for the treatment of pulmonary hypertension

Abstract

Pulmonary hypertension (PH) is a debilitating disease with a poor prognosis. Therapeutic options remain limited despite the introduction of prostacyclin analogues, endothelin receptor antagonists and phosphodiesterase 5 inhibitors within the last 15 years; these interventions address predominantly the endothelial and vascular dysfunctionS associated with the condition, but simply delay progression of the disease rather than offer a cure. In an attempt to improve efficacy, emerging approaches have focused on targeting the pro-proliferative phenotype that underpins the pulmonary vascular remodelling in the lung and contributes to the impaired circulation and right heart failure. Many novel targets have been investigated and validated in animal models of PH, including modulation of guanylate cyclases, phosphodiesterases, tyrosine kinases, Rho kinase, bone morphogenetic proteins signalling, 5-HT, peroxisome proliferator activator receptors and ion channels. In addition, there is hope that combinations of such treatments, harnessing and optimizing vasodilator and anti-proliferative properties, will provide a further, possibly synergistic, increase in efficacy; therapies directed at the right heart may also offer an additional benefit. This overview highlights current therapeutic options, promising new therapies, and provides the rationale for a combination approach to treat the disease.

Figure 1

Current classification of pulmonary hypertension.

Figure 2

Schematic representation of the current and emerging therapeutic targets for pulmonary hypertension outlined in this review. NP, natriuretic peptide; NPR, natriuretic peptide receptor; PGI₂, prostacyclin; ET-1, endothelin-1; BMPR, bone morphogenetic protein receptor; K_v, voltage-sensitive potassium channel; K_ATP, ATP-sensitive potassium channel; TRPC6, transient receptor potential channel C6; VOCC, voltage operated calcium channel; SERT, 5-HT transporter; NEP, neutral endopeptidase; NEPi, NEP inhibitor; BH₄, tetrahydrobiopterin; eNOS, endothelial NO synthase; TKR, tyrosine kinase receptor; ROCK, Rho-associated kinase; sGC, soluble guanylate cyclase; ERA, endothelin receptor antagonist; PDGF, platelet derived growth factor; FGF, fibroblast growth factor; VEGF, vascular endothelial growth factor; AC, adenylate cyclase; IP, prostacyclin receptor; MAPK, mitogen-activated protein kinase; PI3K, phosphoinositide-3-kinase; PKC, protein kinase C; Src, Src kinase; JAK/STAT, Janus kinase/signal transducer and activator of transcription; PDE, phosphodiesterase; PDEi, PDE inhibitor.