Novel Targets of Drug Treatment for Pulmonary Hypertension

Abstract

Biomedical advances over the last decade have identified the central role of proliferative pulmonary arterial smooth muscle cells (PASMCs) in the development of pulmonary hypertension (PH). Furthermore, promoters of proliferation and apoptosis resistance in PASMCs and endothelial cells, such as aberrant signal pathways involving growth factors, G protein-coupled receptors, kinases, and microRNAs, have also been described. As a result of these discoveries, PH is currently divided into subgroups based on the underlying pathology, which allows focused and targeted treatment of the condition. The defining features of PH, which subsequently lead to vascular wall remodeling, are dysregulated proliferation of PASMCs, local inflammation, and apoptosis-resistant endothelial cells. Efforts to assess the relative contributions of these factors have generated several promising targets. This review discusses recent novel targets of therapies for PH that have been developed as a result of these advances, which are now in pre-clinical and clinical trials (e.g., imatinib [phase III]; nilotinib, AT-877ER, rituximab, tacrolimus, paroxetine, sertraline, fluoxetine, bardoxolone methyl [phase II]; and sorafenib, FK506, aviptadil, endothelial progenitor cells (EPCs) [phase I]). While substantial progress has been made in recent years in targeting key molecular pathways, PH still remains without a cure, and these novel therapies provide an important conceptual framework of categorizing patients on the basis of molecular phenotype(s) for effective treatment of the disease.

A Small Molecule Inhibits Deregulated NRF2 Transcriptional Activity in Cancer

“…1 This beneficial effect on cell survival has been exploited clinically as a host of potent KEAP1-reactive electrophiles have been tested or approved for the treatment of various diseases including multiple sclerosis (dimethyl fumarate), cancer prevention (Oltipraz), and pulmonary arterial hypertension (Bardoxolone methyl), among others. [2][3][4] Despite these beneficial effects, a wealth of new evidence has suggested that many human cancers, including those of the lung, breast, colon, ovaries, and pancreas, have mutations which promote the stability and activity of NRF2. 5,6 A number of mechanisms that lead to constitutive NRF2 activity in cancer have been demonstrated, including mutations in KEAP1 and NRF2, mutations in fumarate hydratase leading to KEAP1 succination, KEAP1 promoter hypermethylation, and the expression of oncogenes leading to increased NRF2 transcription.…”

Emerging Metabolic Therapies in Pulmonary Arterial Hypertension

“…The loss of PAECs via BMPR2 mutations contributes to a pro-inflammatory state that would allow for immune cell infiltration, PASMC hyperproliferation, and occlusion of the vessel lumen, which is observed in PAH histology [20]. Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) has been shown to improve mitochondrial function and reduce the generation of ROS and inflammation, while also reducing arterial and RV remodeling [151,152]. Currently, bardoxolone methyl, an inducer of Nrf2, is underway in a phase II clinical study in PAH patients (NCT02036970) [152].…”

Translational Advances in the Field of Pulmonary Hypertension Molecular Medicine of Pulmonary Arterial Hypertension. From Population Genetics to Precision Medicine and Gene Editing

“…These make use of the strong evidence that several varieties of circulating cells, including endothelial progenitor cells and a variety of bone marrow-derived cells, are found in the vicinity of the pulmonary vascular lesions and may play a role in disease etiology or progression (61). Closest to the clinic is use of cellbased therapies for drug delivery.…”