Proteomic analysis of pulmonary arterial hypertension
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ABSTRACT:
SUBMITTER: Qin X
PROVIDER: S-EPMC8482352 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Pulmonary arterial hypertension (PAH) is a rare, fatal, and incurable disorder. Although advances in the understanding of the PAH pathobiology have been seen in recent years, molecular processes underlying heart remodelling over the course of PAH are still insufficiently understood. Therefore, the aim of this study was to investigate myocardial proteomic profile of rats at different stages of monocrotaline-induced PAH. Samples of left and right ventricle (LV and RV) free wall collected from 32 Wistar rats were subjected to proteomic analysis using an isobaric tag for relative quantitation method. Hemodynamic parameters indicated development of mild elevation of pulmonary artery pressure in the early PAH group (27.00?±?4.93 mmHg) and severe elevation in the end-stage PAH group (50.50?±?11.56 mmHg). In early PAH LV myocardium proteins that may be linked to an increase in inflammatory response, apoptosis, glycolytic process and decrease in myocardial structural proteins were differentially expressed compared to controls. During end-stage PAH an increase in proteins associated with apoptosis, fibrosis and cardiomyocyte Ca2+ currents as well as decrease in myocardial structural proteins were observed in LV. In RV during early PAH, especially proteins associated with myocardial structural components and fatty acid beta-oxidation pathway were upregulated. During end-stage PAH significant changes in RV proteins abundance related to the increased myocardial structural components, intensified fibrosis and glycolytic processes as well as decreased proteins related to cardiomyocyte Ca2+ currents were observed. At both PAH stages changes in RV proteins linked to apoptosis inhibition were observed. In conclusion, we identified changes of the levels of several proteins and thus of the metabolic pathways linked to the early and late remodelling of the left and right ventricle over the course of monocrotaline-induced PAH to delineate potential therapeutic targets for the treatment of this severe disease.
| S-EPMC7462861 | biostudies-literature
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: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
2003-11-15 | GSE703 | GEO
Project description:Pulmonary arterial hypertension associated with congenital heart disease (CHD-PAH) has serious consequence and plasma protein profiles in CHD-PAH are unknown. We aimed to reveal the differential plasma proteins in 272 CHD patients with or without PAH. Various types of CHD-PAH were studied. Differential plasma proteins were first detected by iTRAQ proteomic technology and those with significant clinical relevance were selected for further ELISA validation in new cohort of patients. Among the 190 differential plasma proteins detected by iTRAQ, carbamoyl-phosphate synthetase I (CPSI, related to urea cycle and endogenous nitric oxide production) and complement factor H-related protein 2 (CFHR2, related to complement system and coagulant mechanism) were selected for further ELISA validation in new cohort of 152 patients. Both CPSI and CFHR2 were down-regulated with decreased plasma levels (p?<?0.01). Thus, we for the first time in CHD-PAH patients identified a large number of differential plasma proteins. The decreased CPSI expression in CHD-PAH patients may reveal a mechanism related to endogenous nitric oxide and the decrease of CFHR2 protein may demonstrate the deficiency of the immune system and coagulation mechanism. The findings may open a new direction for translational medicine in CHD-PAH with regard to the diagnosis and progress of the disease.
| S-EPMC5122864 | biostudies-other
Project description:BackgroundPulmonary arterial hypertension (PAH) is a progressive and devastating condition characterized by vascular cell proliferation and is associated with several metabolic derangements. We hypothesized that metabolic derangements in PAH can be detected by measuring metabolic by-products in exhaled breath.MethodsWe collected breath and blood samples from patients with PAH at the time of right-sided heart catheterization (n=31) and from healthy control subjects (n=34). Breath was analyzed by selected ion flow tube-mass spectrometry in predetermined training and validation cohorts.ResultsPatients with PAH were 51.5±14 years old, and 27 were women (85%). Control subjects were 38±13 years old, and 22 were women (65%). Discriminant analysis in the training set identified three ion peaks (H3O+29+, NO+56+, and O2+98+) and the variable age that correctly classified 88.9% of the individuals. In an independent validation cohort, 82.8% of the individuals were classified correctly. The concentrations of the volatile organic compounds 2-propanol, acetaldehyde, ammonia, ethanol, pentane, 1-decene, 1-octene, and 2-nonene were different in patients with PAH compared with control subjects. Exhaled ammonia was higher in patients with PAH (median [interquartile range]: 94.7 parts per billion (ppb) [70-129 ppb] vs 60.9 ppb [46-77 ppb], P<.001) and was associated with right atrial pressure (ρ=0.57, P<.001), mean pulmonary artery pressure (ρ=0.43, P=.015), cardiac index by thermodilution (ρ=-0.39, P=.03), pulmonary vascular resistance (ρ=0.40, P=.04), mixed venous oxygen (ρ=-0.59, P<.001), and right ventricular dilation (ρ=0.42, P=.03).ConclusionsBreathprint is different between patients with PAH and healthy control subjects. Several specific compounds, including ammonia, were elevated in the breath of patients with PAH. Exhaled ammonia levels correlated with severity of disease.
| S-EPMC3941248 | biostudies-literature
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:Inflammation and immunity play a causal role in the pathogenesis of pulmonary vascular remodeling and pulmonary arterial hypertension (PAH). However, the pathways and mechanisms by which inflammation and immunity contribute to pulmonary vascular remodeling remain unknown. RNA sequencing was used to analyze the transcriptome in control and rats injected with monocrotaline (MCT) for 1, 2, 3 and 4 weeks. Using the transcriptional profiling of MCT-induced PAH coupled with bioinformatics analysis, we clustered the differentially expressed genes (DEGs) and chose the increased expression patterns associated with inflammatory and immune response. We found the enrichment of Toll-like receptor (TLR) and NOD-like receptor (NLR) pathways and identified NF-κB-mediated inflammatory and immune profiling in MCT-induced PAH. Pathway-based data integration and visualization showed the dysregulated TLR and NLR pathways, including increased expression of TLR2 and NLRP3, and their downstream molecules. Further analysis revealed that the activation of TLR and NLR pathways was associated with upregulation of damage-associated molecular patterns (DAMPs) and RIPK3-mediated necroptosis was involved in the generation of DAMPs in MCT-induced PAH. Collectively, we identify RIPK3-mediated necroptosis and its triggered TLR and NLR pathways in the progression of pulmonary vascular remodeling, thus, providing novel insights into the mechanisms underlying inflammation and immunity in the pathogenesis of PAH.
2020-05-02 | GSE149713 | GEO
Project description:Systemic anticoagulation may be beneficial in pulmonary arterial hypertension, but there is no randomized clinical trial data to guide therapeutic decision making, and current guidelines do not account for patient preferences or quality of life. Decision analytic models to evaluate the potential risks and benefits of systemic anticoagulation in pulmonary arterial hypertension patients, focusing on the benefit in quality-adjusted life years, may be helpful in clarifying this uncertainty. We constructed a 31-state Markov decision analytic model to explore anticoagulation and no anticoagulation strategies. Modeled patient characteristics included gender, use of central catheter-based pulmonary arterial hypertension therapy, type of pulmonary arterial hypertension (idiopathic, idiopathic pulmonary arterial hypertension, or connective-tissue associated, connective tissue disease-pulmonary arterial hypertension), and use of oral contraceptive medication by females. Modeled events included mortality, thromboembolic complications, atrial fibrillation, stroke, and anticoagulation bleeding. Deterministic and probabilistic sensitivity analyses were performed. Anticoagulation was favored in all idiopathic pulmonary arterial hypertension cases, with a gain of 0.43-0.51 quality-adjusted life years, and detrimental in all connective tissue disease-pulmonary arterial hypertension cases, with a loss of 0.66-1.89 quality-adjusted life years. Anticoagulation would need to demonstrate a hazard ratio for pulmonary arterial hypertension mortality of 0.95 or better to be favored. In our model, idiopathic pulmonary arterial hypertension patients benefit from anticoagulation in terms of quality-adjusted life years, and connective tissue disease-pulmonary arterial hypertension patients were harmed, with a hazard ratio for pulmonary arterial hypertension mortality of 0.95 or better being required to favorably impact quality-adjusted life years. These results suggest that anticoagulation significantly improves quality adjusted life years and should be offered to all idiopathic pulmonary arterial hypertension patients. Shared decision models based on these results may help clarify therapeutic decision-making uncertainty in pulmonary arterial hypertension patients.
| S-EPMC6928543 | biostudies-literature
Project description:Right ventricular failure (RVF) is the independent and strongest predictor of mortality in pulmonary arterial hypertension (PAH), but, at present, there are no preventive and therapeutic strategies directly targeting the failing right ventricle (RV). The underlying mechanism of RV hypertrophy (RVH) and dysfunction needs to be explored in depth. In this study, we used myocardial proteomics combined with metabolomics to elucidate potential pathophysiological changes of RV remodeling in a monocrotaline (MCT)-induced PAH rat model. The proteins and metabolites extracted from the RV myocardium were identified using label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS). The bioinformatic analysis indicated that elevated intracellular Ca2+ concentrations and inflammation may contribute to myocardial proliferation and contraction, which may be beneficial for maintaining the compensated state of the RV. In the RVF stage, ferroptosis, mitochondrial metabolic shift, and insulin resistance are significantly involved. Dysregulated iron homeostasis, glutathione metabolism, and lipid peroxidation related to ferroptosis may contribute to RV decompensation. In conclusion, we depicted a proteomic and metabolomic profile of the RV myocardium during the progression of MCT-induced PAH, and also provided the insights for potential therapeutic targets facilitating the retardation or reversal of RV dysfunction in PAH.
| S-EPMC9294162 | biostudies-literature
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.
| S-EPMC7758287 | biostudies-literature