The cancer hypothesis of pulmonary arterial hypertension: the next ten years.
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ABSTRACT:
SUBMITTER: Condon D
PROVIDER: S-EPMC7642842 | biostudies-literature | 2020 Jun
REPOSITORIES: biostudies-literature
Publications
The cancer hypothesis of pulmonary arterial hypertension: the next ten years.
Condon David D Agarwal Stuti S Chakraborty Ananya A de Jesus Perez Vinicio A VA
American journal of physiology. Lung cellular and molecular physiology 20200318 6
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Project description:Microarray analysis of peripheral blood mononuclear (PBMC) cells in pulmonary arterial hypertension. Keywords = mononuclear cells Keywords = gene microarray Keywords = pulmonary arterial hypertension Keywords = Herpesvirus Keywords = biomarker Keywords: other
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Project description:The prognosis of pulmonary arterial hypertension (PAH) remains dismal. Over the years, multiple therapeutic advances have been introduced. This study evaluates the evolution of PAH survival over the past 15 years. We included 293 consecutive adult patients diagnosed with PAH between 2005 and 2019 (median age: 61.8 years, 70.3% female). Patients were divided into three cohorts based on the time of diagnosis: 2005-2009, 2010-2014, and 2015-2019 (2005-2009: n = 56; 2010-2014: n = 111; 2015-2019: n = 126). Transplant-free survival was measured from the date of right heart catheterization until patients reached the composite endpoint of lung transplant or death. Multivariable cox-pulmonary hypertension regression was used to study the effect of the time of diagnosis. The final cox model was fitted in both younger and older patients to evaluate the difference between these groups. During a median follow-up time of 4.1 (interquartile range: 2.2-7.3) years, 9 patients underwent lung transplantation and 151 patients died. The median overall transplant-free survival was 6.2 (5.5-8.0) years. Patients older than 56 years at baseline who were diagnosed in 2005-2009 showed better survival compared to patients diagnosed in 2010-2014 and 2015-2019 with an adjusted hazard ratio of, respectively, 2.12 (1.11-4.03) and 2.83 (1.41-5.69). Patients younger than 56 years showed neither an improved nor deteriorated survival over time. In conclusion, survival in patients with PAH did not improve over time, despite more available therapeutic options. This might be partly due to the changed demographic characteristics of the PAH patients and a still important diagnostic delay.
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Project description:Although multiple gene and protein expression have been extensively profiled in human pulmonary arterial hypertension (PAH), the mechanism for the development and progression of pulmonary hypertension remains elusive. Analysis of the global metabolomic heterogeneity within the pulmonary vascular system leads to a better understanding of disease progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we showed unbiased metabolomic profiles of disrupted glycolysis, increased TCA cycle, and fatty acid metabolites with altered oxidation pathways in the severe human PAH lung. The results suggest that PAH has specific metabolic pathways contributing to increased ATP synthesis for the vascular remodeling process in severe pulmonary hypertension. These identified metabolites may serve as potential biomarkers for the diagnosis of severe PAH. By profiling metabolomic alterations of the PAH lung, we reveal new pathogenic mechanisms of PAH in its later stage, which may differ from the earlier stage of PAH, opening an avenue of exploration for therapeutics that target metabolic pathway alterations in the progression of PAH. Global profiles were determined in human lung tissue and compared across 11 normal and 12 severe pulmonary arterial hypertension patients. Using a combination of microarray and high-throughput liquid-and-gas-chromatography-based mass spectrometry, we showed unbiased metabolomic profiles of disrupted glycolysis, increased TCA cycle, and fatty acid metabolites with altered oxidation pathways in the severe human PAH lung.
2014-11-14 | E-GEOD-53408 | biostudies-arrayexpress
Project description:Arterial pulmonary hypertension is a rare disease, with little knowledge regarding its etiology, and high mortality. Development of right and later on also left ventricular heart insufficiency, secondary to pulmonary hypertension, is a negative predictive factor. Genetic and molecular processes underlying left heart ventricle remodeling over the course of pulmonary hypertension remain unknown. In particular, there is no knowledge regarding the mechanisms of left heart ventricle atrophy which was completely avoided by researchers until recently.The aim of this study was to assess changes in protein abundance in left and right heart ventricle free wall of rats in monocrotaline model of PAH.
2020-09-07 | PXD015896 | Pride
Project description:Although the causal pathomechanisms contributing to remodelling of the pulmonary vascular bed in pulmonary arterial hypertension (PAH) are still unclear, several analogous features with carcinogenesis have led to the emergence of the cancer-like concept. The major similarities concern the altered crosstalk between cells from different tissue types, unexplained proliferation and survival of pulmonary smooth muscle and endothelial cells, the metabolic (glycolytic) shifts, and the association with the immune system. However, major differences between PAH and cancer exist, including the absence of invasion and metastasis, as well as the pathogenic genes involved and the degrees of angiogenesis impairment and genetic instability. It is clear that PAH is not a cancer, but this cancer-like concept has opened a new field of investigation and raises the possibility that antiproliferative and/or oncological drugs may exert therapeutic effects not only in cancer, but also in PAH. Such analogies and differences are discussed here.
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Project description:Pulmonary arterial hypertension (PAH) is a severe and incurable pulmonary vascular disease. One of the primary origins of PAH is pulmonary endothelial dysfunction leading to vasoconstriction, aberrant angiogenesis and smooth muscle cell proliferation, endothelial-to-mesenchymal transition, thrombosis and inflammation. Our objective was to study the epigenetic variations in pulmonary endothelial cells (PEC) through a specific pattern of DNA methylation. DNA was extracted from cultured PEC from patients with idiopathic PAH (n=11), heritable PAH (n=10) and controls (n=18). ). DNA methylation was assessed using the Illumina HumanMethylation450 Assay. After normalization, samples and probes were clustered according to their methylation profile. Differential clusters were functionally analysed using bioinformatics tools.
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Project description:Pulmonary arterial hypertension (PAH) is a disease of the lung blood vessels that results in right heart failure. PAH is thought to occur in about 5% to 10% of patients with hepatosplenic schistosomiasis, particularly due to S. mansoni. The lung blood vessel injury may result from a combination of embolization of eggs through portocaval shunts into the lungs causing localized Type 2 inflammatory response and vessel remodeling, triggering of autonomous pathology that becomes independent of the antigen, and high cardiac output as seen in portopulmonary hypertension. The condition is likely underdiagnosed as there is little systematic screening, and risk factors for developing PAH are not known. Screening is done by echocardiography, and formal diagnosis requires invasive right heart catheterization. Patients with Schistosoma-associated PAH show reduced functional capacity and can be treated with pulmonary vasodilators, which improves symptoms and may improve survival. There are animal models of this disease that might help in understanding disease pathogenesis and identify novel targets to screen and treatment. Pathogenic mechanisms include Type 2 immunity and activation and signaling in the TGF-β pathway. There are still major uncertainties regarding Schistosoma-associated PAH development, course and treatment.
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Project description:Neutrophil elastase (NE) is implicated in pulmonary arterial hypertension (PAH) but the role of neutrophils in the pathogenesis of PAH is unclear. Here we show that neutrophils from PAH vs. control subjects produce and release increased NE associated with enhanced extracellular trap formation. PAH neutrophils are highly adherent and show decreased migration consistent with increased vinculin, identified on proteomic analysis and previously linked to an antiviral response. This was substantiated by a transcriptomic interferon signature in PAH neutrophils and an increase in human endogenous retrovirus (HERV-K) envelope protein. NE and interferon genes are induced by HERV-K envelope and vinculin is increased by HERV-K dUTPase that is elevated in PAH plasma. Neutrophil exosomes from PAH plasma contain increased NE and HERV-K envelope and induce pulmonary hypertension in mice, that is mitigated by the NE inhibitor and antiviral agent, elafin. Thus elevated HERVs explain pathological neutrophils linked to PAH induction and progression.
2023-03-11 | PXD023134 | Pride
Project description:Pulmonary arterial hypertension (PAH) is the best characterized and most studied type of pulmonary hypertension, classified as Group I according to the international guidelines, and hemodinamically defined as pre-capillary pulmonary hypertension. Our analysis was focused on the role of the osteopontin gene in the transcriptional profile of PAH. We used microarray to identifiy the gene expression profiles in patients with PAH and in normal controls.
2018-04-21 | GSE113439 | GEO