Journal Article

Integrative proteomics and phosphoproteomics in pulmonary arterial hypertension

Zhang, Dongmei, Li, Ling, Comhair, Suzy A. A., Cheng, Feixiong, Xu, Weiling, Zhou, Yadi, Asosingh, Kewal, Janocha, Allison J., Hu, Bo, Mavrakis, Lori A., Erzurum, Serpil C., Chen, Ruoying, Willard, Belinda B., Hou, Yuan

2019

Overview

Pulmonary arterial endothelial cells (PAEC) are mechanistically linked to origins of pulmonary arterial hypertension (PAH). Here, global proteomics and phosphoproteomics of PAEC from PAH ( n  = 4) and healthy lungs ( n  = 5) were performed using LC-MS/MS to confirm known pathways and identify new areas of investigation in PAH. Among PAH and control cells, 170 proteins and 240 phosphopeptides were differentially expressed; of these, 45 proteins and 18 phosphopeptides were located in the mitochondria. Pathologic pathways were identified with integrative bioinformatics and human protein-protein interactome network analyses, then confirmed with targeted proteomics in PAH PAEC and non-targeted metabolomics and targeted high-performance liquid chromatography of metabolites in plasma from PAH patients ( n  = 30) and healthy controls ( n  = 12). Dysregulated pathways in PAH include accelerated one carbon metabolism, abnormal tricarboxylic acid (TCA) cycle flux and glutamate metabolism, dysfunctional arginine and nitric oxide pathways, and increased oxidative stress. Functional studies in cells confirmed abnormalities in glucose metabolism, mitochondrial oxygen consumption, and production of reactive oxygen species in PAH. Altogether, the findings indicate that PAH is typified by changes in metabolic pathways that are primarily found in mitochondria.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/106 / 631/45/475/2290 / 631/80/304 / 692/699/1785 / 82/58 / Adult / Arginine / Arginine - metabolism / Bioinformatics / Citric Acid Cycle / Computational Biology / Computer programs / Endothelial cells / Endothelial Cells - metabolism / Female / Glucose - metabolism / High-performance liquid chromatography / Humanities and Social Sciences / Humans / Hypertension / Liquid chromatography / Lung - metabolism / Lung Transplantation / Male / Metabolic pathways / Metabolism / Metabolites / Metabolomics / Middle Aged / Mitochondria / Mitochondria - metabolism / multidisciplinary / Nitric oxide / Nitric Oxide - metabolism / Oxidative Stress / Oxygen consumption / Peptides - metabolism / Phosphoproteins - metabolism / Protein Interaction Mapping / Proteome / Proteomics / Proteomics - methods / Pulmonary Arterial Hypertension - metabolism / Pulmonary hypertension / Reactive oxygen species / Reactive Oxygen Species - metabolism / Science / Science (multidisciplinary) / Tricarboxylic acid cycle