Metabolomics reveals metabolite changes of patients with pulmonary arterial hypertension in China

Chenyang Chen; Fei Luo; Panyun Wu; Yiyuan Huang; Avash Das; Shenglan Chen; Jingyuan Chen; Xinqun Hu; Fei Li; Zhenfei Fang; Shenhua Zhou

doi:10.1111/jcmm.14937

Metabolomics reveals metabolite changes of patients with pulmonary arterial hypertension in China

J Cell Mol Med. 2020 Feb;24(4):2484-2496. doi: 10.1111/jcmm.14937. Epub 2020 Jan 16.

Authors

Chenyang Chen^{1

2}, Fei Luo¹, Panyun Wu¹, Yiyuan Huang¹, Avash Das³, Shenglan Chen¹, Jingyuan Chen¹, Xinqun Hu¹, Fei Li⁴, Zhenfei Fang¹, Shenhua Zhou¹

Affiliations

¹ Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, China.
² Department of Cardiovascular Medicine, The Third Xiangya Hospital, Central South University, Changsha, China.
³ Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁴ Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China.

Abstract

The specific mechanism of pulmonary arterial hypertension (PAH) remains elusive. The present study aimed to explore the underlying mechanism of PAH through the identity of novel biomarkers for PAH using metabolomics approach. Serum samples from 40 patients with idiopathic PAH (IPAH), 20 patients with congenital heart disease-associated PAH (CHD-PAH) and 20 healthy controls were collected and analysed by ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry (UPLC-HRMS). Orthogonal partial least square-discriminate analysis (OPLS-DA) was applied to screen potential biomarkers. These results were validated in monocrotaline (MCT)-induced PAH rat model. The OPLS-DA model was successful in screening distinct metabolite signatures which distinguished IPAH and CHD-PAH patients from healthy controls, respectively (26 and 15 metabolites). Unbiased analysis from OPLS-DA identified 31 metabolites from PAH patients which were differentially regulated compared to the healthy controls. Our analysis showed dysregulation of the different metabolic pathways, including lipid metabolism, glucose metabolism, amino acid metabolism and phospholipid metabolism pathways in PAH patients compared to their healthy counterpart. Among these metabolites from dysregulated metabolic pathways, a panel of metabolites from lipid metabolism and fatty acid oxidation (lysophosphatidylcholine, phosphatidylcholine, perillic acid, palmitoleic acid, N-acetylcholine-d-sphingomyelin, oleic acid, palmitic acid and 2-Octenoylcarnitine metabolites) were found to have a close association with PAH. The results from the analysis of both real-time quantitative PCR and Western blot showed that expression of LDHA, CD36, FASN, PDK1 GLUT1 and CPT-1 in right heart/lung were significantly up-regulated in MCT group than the control group.

Keywords: lipid metabolism; metabolomics; pulmonary arterial hypertension.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Animals
Biomarkers / metabolism
Case-Control Studies
China
Chromatography, High Pressure Liquid / methods
Discriminant Analysis
Familial Primary Pulmonary Hypertension / drug therapy
Familial Primary Pulmonary Hypertension / metabolism*
Fatty Acids / metabolism
Female
Humans
Lipid Metabolism / drug effects
Male
Mass Spectrometry / methods
Metabolic Networks and Pathways / drug effects
Metabolomics / methods
Monocrotaline / pharmacology
Rats
Rats, Sprague-Dawley

Substances

Biomarkers
Fatty Acids
Monocrotaline