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.
Highlights
Pulmonary arterial hypertension (PAH) is characterized by histological changes in the distal pulmonary arteries, such as intimal/medial thickening, and perivascular inflammation and fibrotic change, resulting in right ventricular failure and premature death [1]
We have revealed a protective role of the endogenous erythropoietin (Epo)/Epo receptor (EpoR) system against the development of pulmonary hypertension (PH) [27]
Based on the development of academic drug discovery, we focused on the inhibition of pulmonary artery smooth muscle cells (PASMCs) proliferation to discover a novel drug for Heart failure (HF) with post-capillary PH
Summary
Pulmonary arterial hypertension (PAH) is characterized by histological changes in the distal pulmonary arteries, such as intimal/medial thickening, and perivascular inflammation and fibrotic change, resulting in right ventricular failure and premature death [1]. We have revealed a protective role of the endogenous erythropoietin (Epo)/Epo receptor (EpoR) system against the development of pulmonary hypertension (PH) [27] This system plays a crucial role in the functional recovery of ischemic heart [28] and ischemic lower limb [29], demonstrating the importance of endothelial function and homeostasis [30,31]. The low-dose of aspirin exerts anti-platelet effects in patients with coronary artery disease (CAD), which contributes to the significant improvement of long-term survival in CAD patients [48] When we consider these backgrounds [45,47], it could be possible that the efficacy of aspirin in CAD patients is partially due to its stimulatory effect on endothelial AMPK signaling.
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