Identification of Novel Therapeutic Targets for Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are fatal diseases; however, their pathogenesis still remains to be elucidated. We have recently screened novel pathogenic molecules and have performed drug discovery targeting those molecules. Pulmonary artery smooth muscle cells (PASMCs) in patients with PAH (PAH-PASMCs) have high proliferative properties like cancer cells, which leads to thickening and narrowing of distal pulmonary arteries. Thus, we conducted a comprehensive analysis of PAH-PASMCs and lung tissues to search for novel pathogenic proteins. We validated the pathogenic role of the selected proteins by using tissue-specific knockout mice. To confirm its clinical significance, we used patient-derived blood samples to evaluate the potential as a biomarker for diagnosis and prognosis. Finally, we conducted a high throughput screening and found inhibitors for the pathogenic proteins.

Keywords: biomarker; drug discovery; pathogenesis; pulmonary hypertension.

Figure 1

Screening of novel therapeutic targets for pulmonary arterial hypertension and schematic representation of the role of selenoprotein P (SeP). Volcano plots of gene expression variations in PAH-PASMCs and control PASMCs. Blue plots represent probes for SeP. Dashed lines represent an adjusted P value of 0.05 and ± 1-fold change. PAH-PASMCs, pulmonary artery smooth muscle cells harvested from patients with pulmonary arterial hypertension (PAH); ApoER2, apolipoprotein E receptor 2; ERK1/2, extracellular signal regulated kinases 1 and 2; ETC, electron transport chain; FOXO3a, forkhead box protein O3a; GSH, glutathione; GSSG, oxidized glutathione; HIF-1α, hypoxia inducible factor 1α; PAH-PASMCs, pulmonary arterial hypertension-pulmonary artery smooth muscle cells; ROS, reactive oxygen species; SeP, selenoprotein P; TCA cycle, tricarboxylic acid cycle.