Abstract
Pulmonary arterial hypertension (PAH) is a devastating disease, characterized by obstructive pulmonary vascular remodelling ultimately leading to right ventricular (RV) failure and death. Disturbed transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) signalling, endothelial cell dysfunction, increased proliferation of smooth muscle cells and fibroblasts, and inflammation contribute to this abnormal remodelling. Peptidyl-prolyl isomerase Pin1 has been identified as a critical driver of proliferation and inflammation in vascular cells, but its role in the disturbed TGF-β/BMP signalling, endothelial cell dysfunction, and vascular remodelling in PAH is unknown. Here, we report that Pin1 expression is increased in cultured pulmonary microvascular endothelial cells (MVECs) and lung tissue of PAH patients. Pin1 inhibitor, juglone significantly decreased TGF-β signalling, increased BMP signalling, normalized their hyper-proliferative, and inflammatory phenotype. Juglone treatment reversed vascular remodelling through reducing TGF-β signalling in monocrotaline + shunt-PAH rat model. Juglone treatment decreased Fulton index, but did not affect or harm cardiac function and remodelling in rats with RV pressure load induced by pulmonary artery banding. Our study demonstrates that inhibition of Pin1 reversed the PAH phenotype in PAH MVECs in vitro and in PAH rats in vivo, potentially through modulation of TGF-β/BMP signalling pathways. Selective inhibition of Pin1 could be a novel therapeutic option for the treatment of PAH.
Highlights
Pulmonary arterial hypertension (PAH) is a progressive disorder in which endothelial dysfunction and vascular remodelling obstruct small pulmonary arteries
Rats were randomly assigned to 3 groups: (1) MCT + Shunt sacrificed at T21 (MS21) as a baseline group; (2) treatment with vehicle (5% DMSO in drinking water) from T21, with sacrifice at T35 (MS35Veh); (3) treatment from T21 with 5 mg/kg juglone in vehicle (5%DMSO in drinking water) with sacrifice at T35 (MS35Juglone)
To determine if Pin1 is involved in the pathology of PAH we first performed immunofluorescent analysis of lung of idiopathic patients and showed that the expression of Pin1 is increased when compared to controls (Fig. 1A)
Summary
Pulmonary arterial hypertension (PAH) is a progressive disorder in which endothelial dysfunction and vascular remodelling obstruct small pulmonary arteries. This results in a marked and sustained elevation of pulmonary artery (PA). The abnormal pulmonary vascular remodelling is characterized by a hyperproliferative, apoptosis-resistant and inflammatory phenotype of pulmonary arterial endothelial cells (PAECs) and smooth muscle cells (SMCs) [5,6,7,8,9]. Despite recent advances in the molecular understanding of the vascular remodelling in PAH, current therapies fail to reverse this vascular remodelling, resulting in only a modest improvement in morbidity and mortality. There remains an urgent need to identify new molecular targets that can reverse vascular remodelling to develop effective and safe treatments for PAH patients
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