Journal
ANGIOGENESIS
Volume 25, Issue 1, Pages 99-112Publisher
SPRINGER
DOI: 10.1007/s10456-021-09812-7
Keywords
Pulmonary arterial hypertension; Vascular remodelling; Endothelial cell; TGF-beta; BMP signalling; Inflammation
Categories
Funding
- Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation
- Dutch Federation of University Medical Centers
- Netherlands Organization for Health Research and Development
- Royal Netherlands Academy of Sciences [2012-2008, 2018-2023]
- Stichting Hartekind
- Sebald fund
- Dutch lung foundation [5.2.17.198J0]
- Leiden University Foundation [W18378-2-32]
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Pulmonary arterial hypertension (PAH) is a devastating disease characterized by obstructive pulmonary vascular remodeling. Targeting Pin1 could potentially reverse the phenotype of PAH through modulation of TGF-beta/BMP signaling pathways, providing a novel therapeutic option for PAH treatment.
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-beta (TGF-beta)/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-beta/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-beta signalling, increased BMP signalling, normalized their hyper-proliferative, and inflammatory phenotype. Juglone treatment reversed vascular remodelling through reducing TGF-beta 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-beta/BMP signalling pathways. Selective inhibition of Pin1 could be a novel therapeutic option for the treatment of PAH.
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