Metabolic reprogramming of the urea cycle pathway in experimental pulmonary arterial hypertension rats induced by monocrotaline

Hai-Kuo Zheng,Xiao-Jian Wang,Xiao-Jian Wang,Jun-Han Zhao,Yang-Yang He,Yang-Yang He,Zhi-Cheng Jing,Zhi-Cheng Jing,Jue Ye,Jue Ye,Ping Yang,Ping Yang,Zhe Wang,Yi Yan,Yi Yan,Tian-Yu Lian,Tian-Yu Lian

doi:10.1186/s12931-018-0800-5

Abstract

BackgroundPulmonary arterial hypertension (PAH) is a rare systemic disorder associated with considerable metabolic dysfunction. Although enormous metabolomic studies on PAH have been emerging, research remains lacking on metabolic reprogramming in experimental PAH models. We aim to evaluate the metabolic changes in PAH and provide new insight into endogenous metabolic disorders of PAH.MethodA single subcutaneous injection of monocrotaline (MCT) (60 mg kg− 1) was used for rats to establish PAH model. Hemodynamics and right ventricular hypertrophy were adopted to evaluate the successful establishment of PAH model. Plasma samples were assessed through targeted metabolomic profiling platform to quantify 126 endogenous metabolites. Orthogonal partial least squares discriminant analysis (OPLS-DA) was used to discriminate between MCT-treated model and control groups. Metabolite Set Enrichment Analysis was adapted to exploit the most disturbed metabolic pathways.ResultsEndogenous metabolites of MCT treated PAH model and control group were well profiled using this platform. A total of 13 plasma metabolites were significantly altered between the two groups. Metabolite Set Enrichment Analysis highlighted that a disruption in the urea cycle pathway may contribute to PAH onset. Moreover, five novel potential biomarkers in the urea cycle, adenosine monophosphate, urea, 4-hydroxy-proline, ornithine, N-acetylornithine, and two candidate biomarkers, namely, O-acetylcarnitine and betaine, were found to be highly correlated with PAH.ConclusionThe present study suggests a new role of urea cycle disruption in the pathogenesis of PAH. We also found five urea cycle related biomarkers and another two candidate biomarkers to facilitate early diagnosis of PAH in metabolomic profile.

Highlights

Pulmonary arterial hypertension (PAH) is a rare systemic disorder associated with considerable metabolic dysfunction
Pulmonary arterial hypertension (PAH) is a rare and devastating disease characterized by progressive pulmonary vascular remolding, which leads to right ventricle (RV) failure and death [1, 2]
Establishment of PAH model PAH is characterized by a sustained increase in pulmonary artery pressure and vascular remolding associated with pulmonary arteriole obliteration [17]

Summary

Introduction

Pulmonary arterial hypertension (PAH) is a rare systemic disorder associated with considerable metabolic dysfunction. Pulmonary arterial hypertension (PAH) is a rare and devastating disease characterized by progressive pulmonary vascular remolding, which leads to right ventricle (RV) failure and death [1, 2]. Recent studies have demonstrated the relationship of the metabolic syndrome with PAH and highlighted the features of insulin resistance [7], adiponectin deficiency [8], dyslipidemia [9], fatty acid oxidation, and the tricarboxylic acid cycle [10] in the development of pulmonary vascular disease. The complex pathobiology of PAH involves various metabolic pathways related to inflammation, oxidative stress, plaque composition, and lipid metabolism, leads to endothelial damage, increased pulmonary vascular resistance, and right heart failure [10]. Improved understanding of the specific metabolic pathobiology of PAH is critical in exploring the pathogenesis of PAH and uncovering the novel therapeutic targets for this devastating disease

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