scholarly journals The EYA3 tyrosine phosphatase activity promotes pulmonary vascular remodeling in pulmonary arterial hypertension

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Yuhua Wang ◽  
Ram Naresh Pandey ◽  
Allen J. York ◽  
Jaya Mallela ◽  
William C. Nichols ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Phosphatase Activity ◽  
Vascular Remodeling ◽  
Tyrosine Phosphatase ◽  
Phosphatase Domain ◽  
Eyes Absent ◽  
Pulmonary Arterial ◽  
Inactivating Mutation

Abstract In pulmonary hypertension vascular remodeling leads to narrowing of distal pulmonary arterioles and increased pulmonary vascular resistance. Vascular remodeling is promoted by the survival and proliferation of pulmonary arterial vascular cells in a DNA-damaging, hostile microenvironment. Here we report that levels of Eyes Absent 3 (EYA3) are elevated in pulmonary arterial smooth muscle cells from patients with pulmonary arterial hypertension and that EYA3 tyrosine phosphatase activity promotes the survival of these cells under DNA-damaging conditions. Transgenic mice harboring an inactivating mutation in the EYA3 tyrosine phosphatase domain are significantly protected from vascular remodeling. Pharmacological inhibition of the EYA3 tyrosine phosphatase activity substantially reverses vascular remodeling in a rat model of angio-obliterative pulmonary hypertension. Together these observations establish EYA3 as a disease-modifying target whose function in the pathophysiology of pulmonary arterial hypertension can be targeted by available inhibitors.

scholarly journals AB1139 DIAGNOSTICIS AND PROGNOSTICIS SIGNIFICANCE OF CHEST CT EVALUATION OF SMALL PULMONARY VESSELS IN CONNECTIVE TISSUE DISEASES WITH PULMONARY ARTERIAL HYPERTENSION.

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1859.1-1860
Author(s):  
Y. Zhang ◽  
N. Zhang ◽  
Y. Zhu ◽  
Q. Wang ◽  
L. Zhou
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Connective Tissue ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Connective Tissue Diseases ◽  
Chest Ct ◽  
Pulmonary Vessels ◽  
Ct Evaluation ◽  
Pulmonary Arterial

Background:Pulmonary arterial hypertension (PAH) is a fatal complication of connective tissue diseases (CTDs). Chest CT has been increasingly used in the evaluation of patients with suspected PH noninvasively but there is a paucity of studies.Objectives:Our study was aimed to investigate the cross-sectional area (CSA) of small pulmonary vessels on chest CT for the diagnosis and prognosis of CTD-PAH.Methods:This retrospective study analyzed the data of thirty-four patients with CTD-PAH who were diagnosed by right heart catheterization (RHC) and underwent chest CT between March 2011 and October 2019. We measured the percentage of total CSA of vessels<5 mm2and 5-10 mm2as a percentage of total lung area (%CSA<5and %CSA5-10) on Chest CT. Furthermore, the association of %CSA with mean pulmonary artery pressure (mPAP) was also investigated. Besides, these patients were followed up until October 2019, and Kaplan-Meier survival curves were generated for the evaluation of prognosis.Results:Patients with CTD-PAH had significantly higher %CSA5-10than CTD-nPAH (p=0.001), %CSA5-10in CTD-S-PAH and IPAH was significantly higher than CTD-LM-PAH and COPD-PH (p<0.01). There was a positive correlation between %CSA5-10and mPAP in CTD-PAH (r=0.447, p=0.008). Considering %CSA5-10above 0.38 as a threshold level, the sensitivity and specificity were found to be 0.824 and 0.706, respectively. Patients with %CSA5-10≥0.38 had a lower survival rate than those with %CSA5-10<0.38 (p=0.049).Conclusion:Quantitative parameter, %CSA5-10on Chest CT might serve a crucial differential diagnostic tool for different types of PH. %CSA5-10≥0.38 is a prognostic indicator for evaluation of CTD-PAH.References:[1]Galie N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension. Rev Esp Cardiol (Engl Ed). 2016;69(2):177.[2]Siddiqui I, Rajagopal S, Brucker A, et al. Clinical and Echocardiographic Predictors of Outcomes in Patients With Pulmonary Hypertension. Am J Cardiol. 2018;122(5):872-878.[3]Coste F, Dournes G, Dromer C, et al. CT evaluation of small pulmonary vessels area in patients with COPD with severe pulmonary hypertension. Thorax. 2016;71(9):830-837.[4]Freed BH, Collins JD, Francois CJ, et al. MR and CT Imaging for the Evaluation of Pulmonary Hypertension. JACC Cardiovasc Imaging. 2016;9(6):715-732.[5]Pietra GG, Capron F, Stewart S, et al. Pathologic assessment of vasculopathies in pulmonary hypertension. J Am Coll Cardiol. 2004;43(12 Suppl S):25S-32S.[6]Zanatta E, Polito P, Famoso G, et al. Pulmonary arterial hypertension in connective tissue disorders: Pathophysiology and treatment. Exp Biol Med (Maywood). 2019;244(2):120-131.[7]Rabinovitch M, Guignabert C, Humbert M, Nicolls MR. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res. 2014;115(1):165-175.[8]Thenappan T, Ormiston ML, Ryan JJ, Archer SL. Pulmonary arterial hypertension: pathogenesis and clinical management. BMJ. 2018;360:j5492.[9]Thompson AAR, Lawrie A. Targeting Vascular Remodeling to Treat Pulmonary Arterial Hypertension. Trends Mol Med. 2017;23(1):31-45.[10]Shimoda LA, Laurie SS. Vascular remodeling in pulmonary hypertension. J Mol Med (Berl). 2013;91(3):297-309.[11]Rabinovitch M. Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest. 2012;122(12):4306-4313.[12]Seeger W, Adir Y, Barbera JA, et al. Pulmonary hypertension in chronic lung diseases. J Am Coll Cardiol. 2013;62(25 Suppl):D109-116.Acknowledgments:Thanks to all patients involved in this retrospective study. Thanks go to every participant who participated in this study for their enduring efforts in working with participants to complete the study. Thanks to Liangmin Wei for helping us with statistics analysis.Disclosure of Interests:None declared

scholarly journals The FGL2 prothrombinase contributes to the pathological process of experimental pulmonary hypertension

2019 ◽  
Vol 127 (6) ◽  
pp. 1677-1687
Author(s):  
Cheng Fan ◽  
Jue Wang ◽  
Chaoqin Mao ◽  
Wenzhu Li ◽  
Kun Liu ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Endothelial Dysfunction ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Thrombus Formation ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Potential Therapeutic Target ◽  
Pulmonary Arterial

In situ thrombus formation is one of the major pathological features of pulmonary hypertension (PH). The mechanism of in situ thrombosis has not been clearly identified. Fibrinogen-like protein 2 (FGL2) prothrombinase is an immune coagulant that can cleave prothrombin to thrombin, which then converts fibrinogen into fibrin. This mechanism triggers in situ thrombus formation directly, bypassing both the intrinsic and extrinsic coagulation pathways. FGL2 prothrombinase is mainly expressed in endothelial cells and mediates multiple pathological processes. This implies that it may also play a role in PH. In this study, we examined the expression of FGL2 in idiopathic pulmonary arterial hypertension (IPAH) patients, and in monocrotaline-induced rat and hypoxia-induced mouse PH models. Fgl2−/− mice were used to evaluate the development of PH and explore associated pathological changes. These included in situ thrombosis, vascular remodeling, and endothelial apoptosis. Following these analyses, we examined possible signaling pathways downstream of FGL2 in PH. We show FGL2 is upregulated in pulmonary vascular endothelium in human IPAH and in two animal PH models. Genetic knockout of Fgl2 limited the development of PH, indicated by decreased in situ thrombus formation, less vascular remodeling, and reduced endothelial dysfunction. In addition, loss of FGL2 downregulated PAR1 (proteinase-activated receptor 1) expression and decreased the overactivation and consumption of platelets in hypoxia-induced PH. These results indicate FGL2 participate in the development of PH and loss of FGL2 could attenuate PH by reducing in situ thrombosis and suppressing PAR1 signaling. Thus we provide evidence that suggests FGL2 prothrombinase presents a potential therapeutic target for clinical treatment of PH. NEW & NOTEWORTHY This is the first study to demonstrate that fibrinogen-like protein 2 (FGL2) participates in the pathological progression of pulmonary hypertension (PH) in human idiopathic pulmonary arterial hypertension, a monocrotaline rat PH model, and a hypoxia mouse PH model. Genetic knockout of Fgl2 significantly limited the development of PH indicated by reduced in situ thrombosis, vascular remodeling, and endothelial dysfunction, and suppressed PAR1 (proteinase-activated receptor 1) signaling and overactivation of platelets on PH. These results suggest FGL2 presents a potential therapeutic target for clinical treatment of PH.

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 The Isoquinoline-Sulfonamide Compound H-1337 Attenuates SU5416/Hypoxia-Induced Pulmonary Arterial Hypertension in Rats

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 66
Author(s):  
Hiroki Shoji ◽  
Yoko Yoshida ◽  
Takayuki Jujo Sanada ◽  
Akira Naito ◽  
Junko Maruyama ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Right Ventricle ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Myosin Light Chain ◽  
Pulmonary Vasculature ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Arterial ◽  
Sulfonamide Compound

Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure and right heart failure. Selective pulmonary vasodilators have improved the prognosis of PAH; however, they are not able to reverse pulmonary vascular remodeling. Therefore, a search for new treatment agents is required. H-1337 is an isoquinoline-sulfonamide compound that inhibits multiple serine/threonine kinases, including Rho-associated protein kinase (ROCK) and mammalian target of rapamycin (mTOR). Here, we investigated the effects of H-1337 on pulmonary hypertension and remodeling in the pulmonary vasculature and right ventricle in experimental PAH induced by SU5416 and hypoxia exposure. H-1337 and H-1337M1 exerted inhibitory effects on ROCK and Akt. H-1337 inhibited the phosphorylation of myosin light chain and mTOR and suppressed the proliferation of smooth muscle cells in vitro. H-1337 treatment also suppressed the phosphorylation of myosin light chain and mTOR in the pulmonary vasculature and decreased right ventricular systolic pressure and the extent of occlusive pulmonary vascular lesions. Furthermore, H-1337 suppressed aggravation of right ventricle hypertrophy. In conclusion, our data demonstrated that inhibition of ROCK and mTOR pathways with H-1337 suppressed the progression of pulmonary vascular remodeling, pulmonary hypertension, and right ventricular remodeling.

scholarly journals Hypoxia-Inducible Factor 2-Alpha Mediated Gene Sets Differentiate Pulmonary Arterial Hypertension

2021 ◽  
Vol 9 ◽  
Author(s):  
Jinsheng Zhu ◽  
Li Zhao ◽  
Yadan Hu ◽  
Guoqi Cui ◽  
Ang Luo ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Expression Profile ◽  
Vascular Remodeling ◽  
Human Subjects ◽  
Transcriptome Data ◽  
Gene Sets ◽  
Pulmonary Arterial ◽  
The Impact

ObjectivesHIF2α is of vital importance in the regulation of endothelial dysfunction, cell proliferation, migration, and pulmonary vascular remodeling in pulmonary hypertension. Our previous studies demonstrated that conditional and inducible deletion of HIF2α in mouse lung endothelial cells, dramatically protected the mice against vascular remodeling and the development of pulmonary arterial hypertension (PAH). Here, we provide a novel transcriptome insight into the impact of HIF2α in PAH pathogenesis and the potential to use HIF2α-mediated gene sets to differentiate PAH human subjects.MethodsUsing transcriptome data, we first tapped the value of the difference in gene expression profile between wild type (WT) and Hif2a knockdown (KD) cell lines. We considered the deregulated genes between WT and Hif2a-KD cells as HIF2α influenced genes. By examining the lung tissue transcriptome data set with nine controls and eight PAH patients, we evaluated the HIF2α regulatory network in PAH pathogenesis to further determine the identification ability of HIF2α-mediated gene sets in human PAH subjects. On the other hand, using peripheral blood mononuclear cells (PBMCs) transcriptome data from PAH patients and healthy controls, we further validated the potential of the HIF2α-mediated PBMC gene sets as a possible diagnostic tool for PAH. To verify the ability of HIF2α-mediated gene sets for the identification of PAH, endothelial cell-specific Phd2 knockout mice with spontaneous pulmonary hypertension were used for reverse validation experiments.Results19 identified GO biological process terms were significantly correlated with the genes down-regulated in Hif2a-KD cells, all of which are strongly related to the PAH pathogenesis. We further assessed the discriminative power of these HIF2α-mediated gene sets in PAH human subjects. We found that the expression profile of the HIF2α-mediated gene sets in lung tissues and PBMCs were differentiated both between controls and PAH patients. Further, a significant positive correlation was observed between hypoxia and Phd2 deficiency mediated gene set expression profiles. As expected, 7 of the 19 significantly down-regulated GO terms in Hif2a-KD cells were found to overlap with the up-regulated GO gene sets in Phd2EC–/– mice compared to WT controls, suggesting opposing effects of HIF2α and PHD2 on PAH pathogenesis.ConclusionHIF2α-mediated gene sets may be used to differentiate pulmonary arterial hypertension.

Model Characterization of Pulmonary Arterial Hypertension: Analysis of Lung Pathology with Respect to Human Disease

2020 ◽  
Author(s):  
◽  
Eptisam lambu
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Human Disease ◽  
Vascular Remodeling ◽  
Vascular Wall ◽  
Lung Pathology ◽  
Pulmonary Arterial ◽  
Lung Pathogenesis ◽  
Arterial Endothelial Cells

Pulmonary arterial hypertension (PAH) is a rare multifactorial disease characterized by abnormal high blood pressure in the pulmonary artery, or increased pulmonary vascular resistance (PVR), caused by obstruction in the small arteries of the lung. Increased PVR is also thought to be caused by abnormal vascular remodeling, due to thickening of the pulmonary vascular wall resulting from significant hypertrophy of pulmonary arterial smooth-muscle cells (PASMCs) and increased proliferation/impaired apoptosis of pulmonary arterial endothelial cells (PAECs). Herein, we investigated the mechanisms and explored molecular pathways mediating the lung pathogenesis in two PAH rat models: Monocrotaline (MCT) and Sugen5416/Hypoxia (SuHx). We analyzed these disease models to determine where the vasculature shows the most severe PAH pathology and which model best recapitulates the human disease. We investigated the role vascular remodeling, hypoxia, cell proliferation, apoptosis, DNA damage and inflammation play in the pathogenesis of PAH. Neither model recapitulated all features of the human disease, however each model presented with some of the pathology seen in PAH patients.

Pulmonary Arterial Hypertension: Epidemiology and Registries

2014 ◽  
Vol 13 (1) ◽  
pp. 21-26 ◽  
Author(s):  
Michael D. McGoon ◽  
Marc Humbert
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Task Force ◽  
The World ◽  
Important Means ◽  
Pulmonary Arterial

Registries of pulmonary arterial hypertension (PAH) are important means by which to characterize the presentation and outcome of patients and to provide a basis for predicting the course of the disease. This article summarizes the published conclusions of the World Symposium of Pulmonary Hypertension task force that addressed registries and epidemiology of PAH.

scholarly journals Heart and lung transplantation in pulmonary arterial hypertension related to congenital heart disease: an unusual indication

2020 ◽  
Vol 4 (S1) ◽  
Author(s):  
Rosaria Barracano ◽  
Heba Nashat ◽  
Andrew Constantine ◽  
Konstantinos Dimopoulos
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Lung Transplantation ◽  
Atrial Septal Defect ◽  
Septal Defect ◽  
Pulmonary Vascular Disease ◽  
Eisenmenger Syndrome ◽  
Pulmonary Arterial ◽  
Recurrent Haemoptysis

Abstract Background Eisenmenger syndrome is a multisystem disorder, characterised by a significant cardiac defect, severe pulmonary hypertension and long-standing cyanosis. Despite the availability of pulmonary hypertension therapies and improved supportive care in specialist centres, Eisenmenger patients are still faced with significant morbidity and mortality. Case presentation We describe the case of a 44-year-old woman with Eisenmenger syndrome secondary to a large secundum atrial septal defect. Her pulmonary vascular disease was treated with pulmonary vasodilators, but she experienced a progressive decline in exercise tolerance, increasing atrial arrhythmias, resulting in referral for transplantation. Her condition was complicated by significant recurrent haemoptysis in the context of extremely dilated pulmonary arteries and in-situ thrombosis, which prompted successful heart and lung transplantation. She made a slow recovery but remains well 3 years post-transplant. Conclusions Patients with Eisenmenger syndrome secondary to a pre-tricuspid lesion, such as an atrial septal defect have a natural history that differs to patients with post-tricuspid shunts; the disease tends to present later in life but is more aggressive, prompting early and aggressive medical intervention with pulmonary arterial hypertension therapies. This case illustrates that severe recurrent haemoptysis can be an indication for expediting transplantation in Eisenmenger syndrome patients.

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