Current and future treatments of pulmonary arterial hypertension

aliml

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Therapeutic options for pulmonary arterial hypertension (PAH) have increased over the last decades. The advent of pharmacological therapies targeting the prostacyclin, endothelin, and NO pathways has significantly improved outcomes. However, for the vast majority of patients, PAH remains a life-limiting illness with no prospect of cure. PAH is characterised by pulmonary vascular remodelling. Current research focusses on targeting the underlying pathways of aberrant proliferation, migration, and apoptosis. Despite success in preclinical models, using a plethora of novel approaches targeting cellular GPCRs, ion channels, metabolism, epigenetics, growth factor receptors, transcription factors, and inflammation, successful transfer to human disease with positive outcomes in clinical trials is limited. This review provides an overview of novel targets addressed by clinical trials and gives an outlook on novel preclinical perspectives in PAH.


5-HT (serotonin) has been implicated in the development of PAH since anorexigens, which increase the availability of 5-HT by inducing its release from platelets and inhibiting its reuptake and degradation by MAO, were noted to increase the risk of PAH (Abenhaim et al., 1996). Inhibition of the 5-HT2A and 5-HT2B receptors can inhibit development of PH in mouse models (Delaney et al., 2018; West et al., 2016). Nevertheless, the 5-HT2A and 5-HT2B receptor inhibitor terguride showed no clinical benefit in a Phase 2 study in PAH (Ghofrani et al., ), possibly because the 5-HT1B receptor is the most highly expressed 5-HT receptor in the pulmonary arteries in PAH and mediates PASMC proliferation in humans (Lythgoe et al., 2016). However, pre-specified subgroup analysis indicated an improvement of PVR in patients on PAH background therapy with ERAs (Ghofrani et al., 2012). Thus, further studies are planned with a selective inhibitor of tryptophan hydroxylase 1 (TPH1) which is the rate-limiting enzyme in 5-HT biosynthesis. In preclinical PH models, the TPH1 inhibitor significantly reduced PH and showed an additive effect when applied together with ambrisentan, but not tadalafil (Aiello et al., 2017). A clinical Phase 1 study with the TPH1 inhibitor KAR5585 ( identifier: NCT02746237) showed a good safety profile and a decrease in circulating 5-HT (Paralkar et al., 2017). Furthermore, a trial with the 5-HT uptake inhibitor escitalopram was completed in 2008, but no results were published (ClinicalTrials.gov identifier: NCT00190333). Another trial with the selective 5-HT uptake inhibitor fluoxetine is planned (ClinicalTrials.gov identifier: NCT03638908), although a recent analysis using the “Registry to Evaluate Early and Long-term PAH Disease Management” (REVEAL) showed that incident selective 5-HT uptake inhibitor use was associated with increased mortality and a greater risk of clinical worsening, albeit without adjustment for all confounders (Sadoughi et al., 2013).

The picture of mitochondrial alterations in PH is becoming increasingly detailed, including mitochondrial hyperpolarization, dysbalanced mitochondrial fission and fusion, altered mitochondrial calcium handling due to decreased expression of the mitochondrial calcium uniporter and disturbed interaction with the endoplasmic reticulum, increased glutaminolysis and accumulation of mitochondrial heat shock protein 90 (Boucherat et al., 2018; reviewed in detail in Chan & Rubin, 2017, and Culley & Chan, 2018). Most importantly, a causative role for mitochondrial alterations in the development of PH has been supported by the fact that targeting mitochondrial alterations, for example, using dichloroacetate (DCA), which promotes glucose oxidation, or the mitochondrial fission inhibitor Mdivi or by inhibiting fatty acid oxidation, inhibited PH in animal models (Chan & Rubin, 2017; Culley & Chan, 2018).

Recently, clinical interest in histone deacetylase (HDAC) inhibition in PAH has been rekindled by the discovery that the cytosolic HDAC6 is involved in both pulmonary arterial remodelling and RV failure (Boucherat, Chabot, et al., 2017). This isoenzyme represents an important pharmacological target for selective inhibition that may reduce the toxicity related to the off-target effects of pan-HDAC inhibitors previously described in PAH (Bogaard et al., 2011). Other HDACs known as Sirtuins are also implicated in PAH. The Sirtuins are NAD+-dependent HDACs regulating important metabolic pathways involved in many biological processes such as cell survival, proliferation, apoptosis, DNA repair, and cell metabolism all of which are critical to PAH development. Consistent with these findings, mice lacking SIRT3, a mitochondrial deacetylase, have increased acetylation and inhibition of many mitochondrial enzymes and complexes, suppressing mitochondrial oxidative metabolism. These mice spontaneously develop PH; a loss-of-function SIRT3 polymorphism is associated with PAH development in humans (Paulin et al., 2014). The importance of this metabolism–epigenetics axis has been further highlighted by the recent clinical trial results using DCA, a pyruvate dehydrogenase kinase inhibitor known to promote glucose oxidation (see above). The DCA trial showed that functional variants of SIRT3 and UCP2 largely influenced the clinical and haemodynamic response to DCA (Michelakis et al., 2017). Although not fully understood, the down-regulation of both SIRT1 and SIRT3 in PAH might also result from activation of PARP-1 (Meloche et al., 2014), which could cause depletion of NAD+ (SIRT substrate) levels, which inhibits SIRT1 activity (Meloche et al., 2014). Inhibition of PARP1 in conjunction with standard combination therapy (ERA + PDE5 inhibitor) in an experimental PH model showed greater efficacy than standard combination therapy alone (Meloche et al., 2014), and thus, the U.S. Food and Drug Administration-approved PARP1 inhibitor olaparib is under clinical investigation in the Olaparib for PAH study (OPTION; ClinicalTrials.gov identifier: NCT03782818).

The epigenetic/metabolism/DNA damage response axis described above in PAH is very similar to that described in cancer. This cancer theory of PAH (Boucherat, Vitry, et al., 2017) is further reinforced by the implication of the newly described epigenetic reader, bromodomain-containing protein 4 (BRD4), in PAH. Similar to cancer cells in which BRD4 has been shown to promote several oncogenes implicated in PAH pathogenesis, including c-Myc, B-cell lymphoma 2 (Bcl-2), cyclin-dependent kinase inhibitor 1 (p21), cyclin-dependent kinase inhibitor 1B (p27), Runt-related transcription factor 2 (RUNX2), and FOXM1 (Belkina & Denis, 2012), we recently documented that BRD4 is significantly overexpressed in human PAH, accounting for the up-regulation of the oncogenic NFAT, Bcl-2, Survivin, and p21 and triggering the proliferation/apoptosis imbalance in PAH-PASMCs (Meloche et al., 2015; Meloche et al., 2017). BRD4 was similarly up-regulated in PH rat models in which its inhibition improved pulmonary haemodynamics, RV function, and distal pulmonary arterial remodelling. Although these effects were attributed to the modulation of NFAT, Bcl-2, Survivin, and p21, other mechanisms cannot be excluded. The mechanisms accounting for BRD4 inhibitor efficacy in PAH are the subject of numerous published and ongoing preclinical studies. In addition to its effects on the cancer-like phenotype of PASMCs, the inhibition of autoimmune-mediated/inflammatory vascular injuries, RUNX2-mediated pro-calcification processes, and its influence on metabolism and DNA damage are suggested mechanisms of therapeutic intervention by BRD4 inhibitors in PAH. Recently, a clinically available BRD4 inhibitor reversed PH in two independent animal studies potentially through FOXM1 (Van der Feen et al., 2019). Altogether, these findings support a therapeutic role for BRD4 inhibitors in PAH, which is currently being explored in the Apabetalone for PAH Pilot Study (APPRoAcH-p; ClinicalTrials.gov identifier: NCT03655704).
 

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