scholarly journals Keratin 1: A negative regulator of inflammation and potential treatment for pulmonary arterial hypertension

2020 ◽  
Author(s):  
Jennifer K. Trittmann
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Negative Regulator ◽  
Potential Treatment ◽  
Pulmonary Arterial ◽  
Keratin 1

Abstract 321: Protein Tyrosine Phosphatase 1B: a Novel Regulator of Proliferation and Apoptosis in the Development of Pulmonary Arterial Hypertension

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Shayan Moazeni ◽  
Gregoire Ruffenach ◽  
Shervin Sarji ◽  
Christine Cunningham ◽  
Mylene Vaillancourt ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Protein Tyrosine Phosphatase ◽  
Vascular Remodeling ◽  
Tyrosine Phosphatase ◽  
Negative Regulator ◽  
Protein Tyrosine Phosphatase 1B ◽  
Pulmonary Vascular Remodeling ◽  
Protein Tyrosine ◽  
Pulmonary Arterial

Background: Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling that leads to an increase in pulmonary arterial pressure resulting in right ventricle failure and death. PAH is driven by pulmonary artery smooth muscle cell (PASMC) proliferation and resistance to apoptosis. Protein Tyrosine Phosphatase 1B (PTP1B), a negative regulator for platelet-derived growth factor (PDGF) and BCL-2, has recently been implicated in PAH in humans. While PDGF and BCL-2 are increased in PAH patients, the pathway for regulating BCL-2 and PDGF is poorly understood. We aim to investigate if PTP1B has a role in proliferation and resistance to apoptosis in PAH in human PACMCs and in the Sugen/Hypoxia/Normoxia (Su/Hx/Nx) PH rat model. Method: Adult male Sprague-Dawley rats were treated with single intraperitoneal dose of SU5416 (20 mg/kg) and kept in Hx for 3 weeks followed by Nx for 2 weeks. Saline treated rats kept in Nx for 5 weeks served as control (n=4/group). RV catheterization was performed terminally for recording RV systolic pressure (RVSP). RV, LV, and interventricular septum (IVS) were isolated for Fulton index (FI, RV/IVS+LV). We analyzed gene expression in lungs via qPCR. Healthy hPASMCs were incubated with a PTP1B inhibitor (Ethyl-3,4-dephostatin) at IC50=0.58ug/ml for 24hrs under Nx conditions and cells were stained with Ki67 to assess proliferation. Results: Su/Hx/Nx rats had severe PH evidenced by a significantly elevated RVSP compared to control (88.97+/- 13.67 vs 28.47+/- 2.22 mmHg, p<0.05). PH rats also showed severely reduced RV function and increased RV hypertrophy (FI= 0.7+/- 0.063 vs 0.274 +/-0.01, p<0.05). PH lungs exhibited severe pulmonary vascular remodeling with excessive growth of the PASMCs. PTP1B was significantly decreased in PH lungs compared to controls (0.158+/-0.0647 vs 1+/-0.06, P<0.05). BCL-2 expression was significantly increased in PAH compared to control (2.01+/-0.162 vs 1 +/-0.1, P<0.01). Inhibition of PTP1B in cultured hPASMCs increased proliferation by ~2 fold as assessed by Ki67 positive cells (n=3). Conclusion: Severe angioproliferative PH in rats is associated with a downregulation of PTP1B and increased expression of BCL-2 and PASMC proliferation.

scholarly journals PAI-1 is a novel component of the miR-17~92 signaling that regulates pulmonary artery smooth muscle cell phenotypes

2018 ◽  
Vol 315 (2) ◽  
pp. L149-L161 ◽  
Author(s):  
Tianji Chen ◽  
Jason B. Huang ◽  
Jingbo Dai ◽  
Qiyuan Zhou ◽  
J. Usha Raj ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Negative Regulator ◽  
Plasminogen Activator Inhibitor 1 ◽  
Contractile Phenotype ◽  
Pulmonary Arterial ◽  
Pulmonary Artery Smooth Muscle ◽  
Pai 1

We have previously reported that miR-17~92 is critically involved in the pathogenesis of pulmonary hypertension (PH). We also identified two novel mR-17/20a direct targets, PDZ and LIM domain protein 5 (PDLIM5) and prolyl hydroxylase 2 (PHD2), and elucidated the signaling pathways by which PDLIM5 and PHD2 regulate functions of pulmonary artery smooth muscle cells (PASMCs). In addition, we have shown that plasminogen activator inhibitor-1 (PAI-1) is also downregulated in PASMCs that overexpress miR-17~92. However, it is unclear whether PAI-1 is a direct target of miR-17~92 and whether it plays a role in regulating the PASMC phenotype. In this study, we have identified PAI-1 as a novel target of miR-19a/b, two members of the miR-17~92 cluster. We found that the 3′-untranslated region (UTR) of PAI-1 contains a miR-19a/b binding site and that miR-19a/b can target this site to suppress PAI-1 protein expression. MiR-17/20a, two other members of miR-17~92, may also indirectly suppress PAI-1 expression through PDLIM5. PAI-1 is a negative regulator of miR-17~92-mediated PASMC proliferation. Silencing of PAI-1 induces Smad2/calponin signaling in PASMCs, suggesting that PAI-1 is a negative regulator of the PASMC contractile phenotype. We also found that PAI-1 is essential for the metabolic gene expression in PASMCs. Furthermore, although there is no significant change in PAI-1 levels in PASMCs isolated from idiopathic pulmonary arterial hypertension and associated pulmonary arterial hypertension patients, PAI-1 is downregulated in hypoxia/Sugen-induced hypertensive rat lungs. These results suggest that miR-17~92 regulates the PASMC contractile phenotype and proliferation coordinately and synergistically by direct and indirect targeting of PAI-1.

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