Metabolomics-based mechanism exploration of pulmonary arterial hypertension pathogenesis: novel lessons from explanted human lungs

Abstract

Background: Metabolic pathways have been shown to participate in the pathogenesis of pulmonary arterial hypertension (PAH). We investigated the metabolic pro le shifts to reveal molecular mechanisms underlying PAH.Methods: Explanted human lung tissues from 18 PAH patients were collected. The lung tissues far from the tumor from 16 lung cancer patients were taken as controls. Lung tissues were analyzed by LC-MS/MS based non-target metabolomics method. Pathway analysis was performed with KEGG database and MetaboAnalyst 5.0. Statistical analysis including partial least squares discriminant analysis (PLS-DA), Student's t-test, Pearson's correlation, Chi-square test and Fisher's exact probability test were used. COX survival analysis model was applied to evaluate the predictive value of metabolites on prognosis. Protein expression levels were detected by Western blotting in human PAH lung tissues, rat monocrotaline-PAH lungs and hypoxia exposed human pulmonary artery smooth muscle cells (HPASMCs) to study the molecular mechanisms.Results: Signi cant differences in metabolites and metabolic pathways were identi ed among PAH subgroups and control tissues. Spermine levels were positively correlated with the patients' cardiac outputs (COs). Levels of (2e)-2,5-dichloro-4-oxo-2-hexenedioic acid were positively correlated with the patient's serum creatinine (Scr) levels. Patients with higher levels of thymine had a better prognosis. Moreover, 7 differential metabolites were associated with AKT pathway. AKT pathway inactivation was con rmed in human and rat PAH lungs and hypoxia exposed HPASMCs.Conclusions: Our ndings provide the rst metabolomics evidence for PAH pathogenesis by human lungs and may contribute to the improvement of therapeutic strategy.

Metabolomics in Pulmonary Hypertension—A Useful Tool to Provide Insights into the Dark Side of a Tricky Pathology

“…The higher the thymine level, the better the patient prognosis. A direct proportion was found between the spermine level and the patients' cardiac function [48].…”

Interleukin-6 and pulmonary hypertension: from physiopathology to therapy

“…Ding et al. found that the AKT pathway is inactivated in PASMCs exposed to hypoxia as well as in human and rat pulmonary hypertensive lungs ( 172 ). We hypothesize that in the early stage of PH, the body inhibits the PI3K/AKT signaling pathway to prevent activation of its downstream pathway from aggravating disease progression.…”

Integrated Analysis of Transcriptome and Metabolome Provides Insight into Camellia oleifera Oil Alleviating Fat Accumulation in High-Fat Caenorhabditis elegans

“…A pooled quality control (QC) sample was prepared by mixing equal volumes of each extracted supernatant and injected every 10 samples. The metabolites were separated and detected using Waters 2D UPLC (waters, USA) tandem Q exactive high-resolution mass spectrometer (Thermo Fisher Scientific, USA) [50]. Chromatographic separation was conducted using a BEH C18 column (1.7 µm; 2.1 mm × 100 mm, Waters, Milford, MA, USA).…”