Systemic Analysis of Metabolic Products and Related Gene Expression in Human Lung of Pulmonary Arterial Hypertension Using Ultrahigh Performance Liquid Chromatography and Microarray

Abstract

Purpose Pulmonary arterial hypertension (PAH) is a lethal syndrome characterized by vascular obstruction and right ventricular failure. Currently there is no systemic study to disclose abnormal metabolic pathways for PAH. We hypothesized that analysis of the global metabolome and related gene expression in PAH will disclose multiple metabolic changes in PAH disease. The goal of this study was to characterize biochemical and gene profiles observed in lung tissue samples collected from PAH patients after lung transplantation. Methods and Materials Global biochemical genetic profiles were determined and compared across the normal (n=8) and PAH (n=8) cohorts. The normal and PAH lung samples from lung Tx were analyzed on the GC/MS and LC/MS/MS platforms. Welch’s two-sample t-test was used to identify biochemical between experimental groups. mRNA from normal and native PAH lung were isolated and Affymetrix HGU133 Plus 2 arrays were run for each array of independently patient lung sample ( P Results The present dataset comprises a total of 376 compounds of identified biochemical. The PAH tissue showed 93 compounds exhibited altered metabolites (p ≤ 0.05) and were marked by changes in arginine and glucose metabolism, disruptions in mitochondrial oxidation and the TCA cycle, and alterations in bile acids, heme metabolism, oxidative stress, and inflammation compared to healthy subjects. There are significant expression changes of the genes encoding to the key enzymes of the entire metabolisms in PAH. Conclusions The altered PAH metabolisms are correlated with metabolic enzyme related gene expression that lead to the aberrant production or consumption of glucose, amino acids, nucleotides, and lipids. The abnormal regulation of widespread metabolic pathways in PAH may be an important part of PAH pathogenesis. Designing a new strategy for therapeutic targets on the multiple metabolic pathways may open new revenue of treatment of PAH in the future.