Proteomic Analysis of Lung Tissues From Patients With Pulmonary Arterial Hypertension

Abdul-Salam, Vahitha B.; Wharton, John; Cupitt, John; Berryman, Mark; Edwards, Robert J.; Wilkins, Martin R.

doi:10.1161/circulationaha.110.972745

Cited by 109 publications

(104 citation statements)

References 43 publications

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“…Downregulated proteins included guanine nucleotide-binding protein subunit β2 and cAMP-dependent protein kinase type-Iα regulatory subunit, both of which mediate homeostatic signaling in ECs. 37 Downregulation of a guanine nucleotide-binding protein subunit was also found by a 1-dimensional proteomic analysis of PAH lung tissue conducted by Abdul-Salam et al 38 ; however, in this case, it was the α1 rather than the β2 subunit. Chloride intracellular channel proteins 1 and 4 were also increased in PAH lung tissue in the previous study.…”

Section: Discussionmentioning

confidence: 64%

Proteomic Analysis Implicates Translationally Controlled Tumor Protein as a Novel Mediator of Occlusive Vascular Remodeling in Pulmonary Arterial Hypertension

et al. 2014

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Although the genetic basis of PAH is known in some cases, the underlying mechanisms that link loss-of-function mutations in BMPR2 with the development of PAH and its characteristic lung vascular lesions are still unclear. Clinical Perspective on p 2135EC injury and apoptosis are key triggers for the development of PAH. Treatment of rats with a vascular endothelial growth factor receptor antagonist, SU5416, together with a period of chronic hypoxia, 9,10 results in a model of severe, Background-Pulmonary arterial hypertension (PAH) is a lethal disease characterized by excessive proliferation of pulmonary vascular endothelial cells (ECs). Hereditary PAH (HPAH)is often caused by mutations in the bone morphogenetic protein receptor type 2 gene (BMPR2). However, the mechanisms by which these mutations cause PAH remain unclear. Therefore, we screened for dysregulated proteins in blood-outgrowth ECs of HPAH patients with BMPR2 mutations compared with healthy control subjects. Methods and Results-A total of 416 proteins were detected with 2-dimensional PAGE in combination with liquid chromatography/tandem mass spectrometry analysis, of which 22 exhibited significantly altered abundance in bloodoutgrowth ECs from patients with HPAH. One of these proteins, translationally controlled tumor protein (TCTP), was selected for further study because of its well-established role in promoting tumor cell growth and survival. Immunostaining showed marked upregulation of TCTP in lungs from patients with HPAH and idiopathic PAH, associated with remodeled vessels of complex lesions. Increased TCTP expression was also evident in the SU5416 rat model of severe and irreversible PAH, associated with intimal lesions, colocalizing with proliferating ECs and the adventitia of remodeled vessels but not in the vascular media. Furthermore, silencing of TCTP expression increased apoptosis and abrogated the hyperproliferative phenotype of blood-outgrowth ECs from patients with HPAH, raising the possibility that TCTP may be a link in the emergence of apoptosis-resistant, hyperproliferative vascular cells after EC apoptosis. The critical role of EC apoptosis as a trigger in experimental models of PAH is also supported by the efficacy of EC growth and survival factors (eg, vascular endothelial growth factor and angiopoietin-1) in monocrotalineinduced PAH. 13,14 The possible relevance of this paradigm for human PAH is supported by the observation that silencing of BMPR2 15 or overexpression of mutant BMPR2 in human ECs 16 increases apoptosis. Conclusion-ProteomicThe lack of availability of lung tissue from early-stage disease represents a significant limitation for unraveling the initiating mechanisms of human PAH. The selection pressures exerted on resident lung ECs make it is difficult to separate the direct effects of BMPR2 mutations on EC biology from reactive changes in response to the abnormal growth and survival influences of the lung PAH milieu. Recently, it has been recognized that cells with an endothelial phenotype nearly identical to that...

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Section: Discussionmentioning

confidence: 64%

Proteomic Analysis Implicates Translationally Controlled Tumor Protein as a Novel Mediator of Occlusive Vascular Remodeling in Pulmonary Arterial Hypertension

et al. 2014

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“…This results in increased vascular smooth muscle proliferation and development of a PAH phenotype [2]. RAGE is important because it is one of the most up-regulated genes in PAH [23]. Ligands of RAGE include S100A4 which belongs to the family of EF-hand calcium-binding proteins [24] and inhibition of RAGE reverses the PAH phenotype in monocrotaline-and Sugen-induced rodent models [2].…”

Section: Sphingosine Kinase 1 and Hypertensionmentioning

confidence: 99%

Sphingosine Kinase 1: A Potential Therapeutic Target in Pulmonary Arterial Hypertension?

Pyne

2017

Trends in Molecular Medicine

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This version is available at https://strathprints.strath.ac.uk/61649/ Strathprints is designed to allow users to access the research output of the University of Strathclyde. Unless otherwise explicitly stated on the manuscript, Copyright © and Moral Rights for the papers on this site are retained by the individual authors and/or other copyright owners. Please check the manuscript for details of any other licences that may have been applied. You may not engage in further distribution of the material for any profitmaking activities or any commercial gain. You may freely distribute both the url (https://strathprints.strath.ac.uk/) and the content of this paper for research or private study, educational, or not-for-profit purposes without prior permission or charge.Any correspondence concerning this service should be sent to the Strathprints administrator: strathprints@strath.ac.ukThe Strathprints institutional repository (https://strathprints.strath.ac.uk) is a digital archive of University of Strathclyde research outputs. It has been developed to disseminate open access research outputs, expose data about those outputs, and enable the management and persistent access to Strathclyde's intellectual output. Abstract--Sphingosine kinase 1 (SphK1) knockout mice are protected against pulmonary hypertension and expression levels of the enzyme are increased in the lungs of pulmonary arterial hypertensive (PAH) patients. Moreover, sphingosine 1-phosphate can promote vascular remodeling/vasoconstriction in rodent and human pulmonary arterial smooth muscle cell models. Therefore, SphK1 might be a novel target for treatment of PAH.

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“…Increased expression of chloride intracellular channel 4 may be pertinent to the disorganized angiogenesis of plexiform lesions. 12 …”

Section: Discussionmentioning

confidence: 99%

Pulmonary Hypertension in Circulation and the Circulation Subspecialty Journals

2012

Circulation

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The following articles are being highlighted as part of Circulation's Topic Review series. This series will summarize the most important manuscripts, as selected by the editors, published in Circulation and the Circulation subspecialty journals. The studies included in this article represent the articles related to pulmonary hypertension that were published in Circulation and the Circulation subspecialty journals in . (Circulation. 2012125:e645-e652.) Nitrite Potently Inhibits Hypoxic and Inflammatory Pulmonary Arterial Hypertension and Smooth Muscle Proliferation via Xanthine Oxidoreductase-Dependent Nitric Oxide GenerationSummary: Pulmonary arterial hypertension is a disease of the small pulmonary arteries that is characterized by progressive pulmonary vascular remodeling, vasoconstriction, and thrombosis. These changes lead to increased pulmonary vascular pressures and cause right heart failure, which leads to death. In general, therapies have not been effective in reversing the pathophysiological changes associated with pulmonary arterial hypertension. Our investigations define inhaled nebulized sodium nitrite as a potential therapy for pulmonary arterial hypertension. These data demonstrate that sodium nitrite can prevent or reverse pulmonary arterial hypertension in multiple experimental animal models of this disease process. Furthermore, these data show that nitrite is enzymatically converted to vasoactive nitric oxide in lung tissue and pulmonary artery smooth muscle cells via xanthine oxidoreductase. These findings help to define a therapy that may be useful in the treatment of patients with this insidious disease that to this point has lacked effective pharmacological therapies.Conclusion: These studies reveal a potent effect of inhaled nitrite that limits pathological pulmonary arterial hypertrophy and cellular proliferation in the setting of experimental pulmonary arterial hypertension. 1 Ventricular Geometry, Strain, and Rotational Mechanics in Pulmonary HypertensionSummary: As a result of ventricular interdependence, analysis of concomitant intrinsic left ventricular (LV) diseases (ie, myocardial fibrosis) in patients with significant pulmonary hypertension (PH) is challenging. The farther a region is from the right ventricle (eg, the lateral wall), the less the impact will be that the PH has on LV strain. Furthermore, parameters based on circumferential fibers appear to propagate farther from the right ventricle than longitudinal parameters, likely reflecting continuity of the circumferential fibers from the septum to the lateral wall. Accordingly, a finding of abnormal LV lateral wall longitudinal strain in patients with PH might identify true LV dysfunction that is independent of PH. We further demonstrated that LV torsion correlated negatively with estimated pulmonary artery systolic pressure and with septal flattening. Abnormally reduced LV torsion in PH could represent an advanced stage of PH and geometric alteration. Interestingly, although torsion was reduced, untwisting velocity was s...

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Proteomic Analysis of Lung Tissues From Patients With Pulmonary Arterial Hypertension

Cited by 109 publications

References 43 publications

Proteomic Analysis Implicates Translationally Controlled Tumor Protein as a Novel Mediator of Occlusive Vascular Remodeling in Pulmonary Arterial Hypertension

Proteomic Analysis Implicates Translationally Controlled Tumor Protein as a Novel Mediator of Occlusive Vascular Remodeling in Pulmonary Arterial Hypertension

Sphingosine Kinase 1: A Potential Therapeutic Target in Pulmonary Arterial Hypertension?

Pulmonary Hypertension in Circulation and the Circulation Subspecialty Journals

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