Background: Metabonomics has been widely used to analyze the initiation, progress, and development of diseases. However, application of metabonomics to explore the mechanism of pulmonary arterial hypertension (PAH) are poorly reported. This study aimed to investigate the influence of atorvastatin (Ato) on metabolic pattern of rats with pulmonary hypertension. Methods: PAH animal model was established using monocrotaline (MCT). The mean pulmonary artery pressure (mPAP) and right ventricular hypertrophy index (RVHI) were measured. The microstructure of pulmonary arterioles was observed by HE staining. Nuclear magnetic resonance was used to detect and analyze the serum metabolites. The levels of glycogen synthase kinase-3β (GSK-3β), hexokinase 2 (HK-2), sterol regulatory element-binding protein 1c (SREBP-1c), and carnitine palmitoyltransferase I (CPT-1) in the lung tissues were measured. Results: Ato significantly improved lung function by decreasing mPAP, RVHI, wall thickness, and wall area. Differences in metabolic patterns were observed among normal, PAH, and Ato group. The levels of GSK-3β and SREBP-1c were decreased, but HK-2 and CPT-1 were increased in the group PAH. Ato treatment markedly reversed the influence of MCT. Conclusion: Ato significantly improved the pulmonary vascular remodeling and pulmonary hypertension of PAH rats due to its inhibition on Warburg effect and fatty acid β oxidation.
Obesity and overweight are closely related to cardiovascular mortality. Arterial stiffness is one of the important risks for cardiovascular diseases and is strongly related with the cardiovascular mortality. However, the relationship between obesity and arterial stiffness is still controversial. A cross-sectional study was performed to examine the relationship of body fat percentage (BFP), an indicator of obesity, with carotidfemoral pulse wave velocity (cfPWV) in 2603 subjects (aged 58.62 ± 11.27 years, male 71.07%, hypertension 64.89%). All participants were divided into four groups according to the gender and the presence of arterial stiffening based on a value ≥10 m/s of cfPWV(group1 : male with cfPWV <10 m/s, group2 : male with cfPWV ≥10 m/s, group3 : female with cfPWV <10 m/s, group4 : female with cfPWV ≥10 m/s). Body weight, height, waist circumference, blood pressure were measured and clinical biochemical tests were recorded. cfPWV was measured using a non-invasive automatic device (Complior Analysis, France). BFP were calculated by CUN-BAE equation. The level of cfPWV was significantly increased with the increasing trend of BFP in both males and females. Stepwise multiple regression analysis revealed that SBP, DBP, HR, Hcy, BFP, FPG were independent associated with cfPWV in females and SBP, eGFR, FPG, BFP, DBP were independent associated with cfPWV in males. In the subgroups stratified by age, BFP was correlated with cfPWV only in females over 60 years old, but not in female those aged under 60 years old and males. In addition to the age and blood pressure, BFP was one of important predictor of arterial stiffening special in females aged over 60 years old.
Background Pulmonary arterial hypertension (PAH) is a pathophysiological syndrome, characterized by pulmonary vascular remodeling. Immunity and inflammation are progressively recognized properties of PAH, which are crucial for the initiation and maintenance of pulmonary vascular remodeling. This study explored immune cell infiltration characteristics and potential biomarkers of PAH using comprehensive bioinformatics analysis. Methods Microarray data of GSE117261, GSE113439 and GSE53408 datasets were downloaded from Gene Expression Omnibus database. The differentially expressed genes (DEGs) were identified in GSE117261 dataset. The proportions of infiltrated immune cells were evaluated by CIBERSORT algorithm. Feature genes of PAH were selected by least absolute shrinkage and selection operator (LASSO) regression analysis and validated by fivefold cross-validation, random forest and logistic regression. The GSE113439 and GSE53408 datasets were used as validation sets and logistic regression and receiver operating characteristic (ROC) curve analysis were performed to evaluate the prediction value of PAH. The PAH-associated module was identified by weighted gene association network analysis (WGCNA). The intersection of genes in the modules screened and DEGs was used to construct protein–protein interaction (PPI) network and the core genes were selected. After the intersection of feature genes and core genes, the hub genes were identified. The correlation between hub genes and immune cell infiltration was analyzed by Pearson correlation analysis. The expression level of LTBP1 in the lungs of monocrotaline-induced PAH rats was determined by Western blotting. The localization of LTBP1 and CD4 in lungs of PAH was assayed by immunofluorescence. Results A total of 419 DEGs were identified, including 223 upregulated genes and 196 downregulated genes. Functional enrichment analysis revealed that a significant enrichment in inflammation, immune response, and transforming growth factor β (TGFβ) signaling pathway. CIBERSORT analysis showed that ten significantly different types of immune cells were identified between PAH and control. Resting memory CD4+ T cells, CD8+ T cells, γδ T cells, M1 macrophages, and resting mast cells in the lungs of PAH patients were significantly higher than control. Seventeen feature genes were identified by LASSO regression for PAH prediction. WGCNA identified 15 co-expression modules. PPI network was constructed and 100 core genes were obtained. Complement C3b/C4b receptor 1 (CR1), thioredoxin reductase 1 (TXNRD1), latent TGFβ binding protein 1 (LTBP1), and toll-like receptor 1 (TLR1) were identified as hub genes and LTBP1 has the highest diagnostic efficacy for PAH (AUC = 0.968). Pearson correlation analysis showed that LTBP1 was positively correlated with resting memory CD4+ T cells, but negatively correlated with monocytes and neutrophils. Western blotting showed that the protein level of LTBP1 was increased in the lungs of monocrotaline-induced PAH rats. Immunofluorescence of lung tissues from rats with PAH showed increased expression of LTBP1 in pulmonary arteries as compared to control and LTBP1 was partly colocalized with CD4+ cells in the lungs. Conclusion LTBP1 was correlated with immune cell infiltration and identified as the critical diagnostic maker for PAH.
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