Inhibition of the prolyl isomerase Pin1 improves endothelial function and attenuates vascular remodelling in pulmonary hypertension by inhibiting TGF-β signalling

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.

Therapeutic Approaches in Pulmonary Arterial Hypertension with Beneficial Effects on Right Ventricular Function—Preclinical Studies

“…Nineteen studies were selected after applying the exclusion and inclusion criteria (Figure 1) [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31]. They were published between 2009 and 2022, providing data for twenty drugs and two combinations of two drugs, with a great variety of mechanisms of action (Table 1).…”

“…All MCT animals were rats (Table 2) and a single MCT dose of 60 mg/Kg was administered, except in one study (30 mg/Kg) [16], to induce PH. In two studies, rats further underwent aortocaval shunt surgery (MCT + S) [19,31]. Other models underwent hypoxia periods: CH and SuHx (Table 3).…”

Bioinformatics analysis of the immune cell infiltration characteristics and correlation with crucial diagnostic markers in pulmonary arterial hypertension

“…TGFβ signaling pathway was overactivated and leads to excessive proliferation and resistance of apoptosis [ 27 , 28 ]. TGF-β1 is an essential regulator of extracellular matrix (ECM) deposition, promoting fibrosis and inflammation [ 29 ]. These studies confirmed that the immune response and inflammation play important roles in PAH.…”

“…Leppäranta et al [ 35 ] reported that LTBP1 was significantly upregulated inidiopathic pulmonary fibrosis (IPF) patient lungs and modulated TGF-β availability and activation in different pulmonary compartments in the fibrotic lung. TGFβ signaling pathway was overactivated in PAH and lead to excessive proliferation, the resistance of apoptosis and ECM deposition [ 29 , 30 ]. ECM deposition in remodeling pulmonary arteries is thought to be a key characteristic of PAH.…”

Pin1 as Molecular Switch in Vascular Endothelium: Notes on Its Putative Role in Age-Associated Vascular Diseases

“…Pin1 has been found to act as a critical driver of vascular cell proliferation, apoptosis, and inflammation, with implication in many cardiovascular diseases (e.g., atherosclerosis, coronary restenosis, and cardiac hypertrophy) [ 10 , 11 , 12 ]. Notably, Pin1 has been reported to regulate the degradation of the inducible nitric oxide synthase (iNOS) in murine aortic endothelial cells upon induction by lipopolysaccharide and IFN-γ [ 13 ], as well as to interact with eNOS in a phosphorylation-dependent manner, thereby suppressing eNOS activity, similar to the tonic suppression of eNOS activity by caveolin-1 [ 14 ].…”