Metabolomic analysis of bone morphogenetic protein receptor type 2 mutations in human pulmonary endothelium reveals widespread metabolic reprogramming

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease of the lung vasculature for which the molecular etiologies are unclear. Specific metabolic alterations have been identified in animal models and in PAH patients, though existing data focus mainly on abnormalities of glucose hom...

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Published in:	Pulmonary circulation Vol. 2; no. 2; pp. 201 - 213
Main Authors:	Fessel, Joshua P., Hamid, Rizwan, Wittmann, Bryan M., Robinson, Linda J., Blackwell, Tom, Tada, Yuj, Tanabe, Nobuhiro, Tatsumi, Koichiro, Hemnes, Anna R., West, James D.
Format:	Journal Article
Language:	English
Published:	London, England University of Chicago Press 01-04-2012 SAGE Publications Sage Publications Ltd. (UK) John Wiley & Sons, Inc Medknow Publications & Media Pvt Ltd
Subjects:	anaplerosis BMPR2 Bone morphogenetic proteins Dehydrogenases Endothelial cells Fatty acids Gene mutations Genes Genetic aspects Genetic mutation Glycolysis Health aspects isocitrate dehydrogenase Lipid metabolism Metabolic diseases Metabolism Metabolomics Mutation Oxidation Pathogenesis Physiological aspects pulmonary arterial hypertension Pulmonary hypertension Research Article Vascular endothelium Warburg effect United States BMPR2 isocitrate dehydrogenase pulmonary arterial hypertension anaplerosis Warburg effect
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Summary:	Pulmonary arterial hypertension (PAH) is a progressive and fatal disease of the lung vasculature for which the molecular etiologies are unclear. Specific metabolic alterations have been identified in animal models and in PAH patients, though existing data focus mainly on abnormalities of glucose homeostasis. We hypothesized that analysis of the entire metabolome in PAH would reveal multiple other metabolic changes relevant to disease pathogenesis and possible treatment. Layered transcriptomic and metabolomic analyses of human pulmonary microvascular endothelial cells (hPMVEC) expressing two different disease-causing mutations in the bone morphogenetic protein receptor type 2 (BMPR2) confirmed previously described increases in aerobic glycolysis but also uncovered significant upregulation of the pentose phosphate pathway, increases in nucleotide salvage and polyamine biosynthesis pathways, decreases in carnitine and fatty acid oxidation pathways, and major impairment of the tricarboxylic acid (TCA) cycle and failure of anaplerosis. As a proof of principle, we focused on the TCA cycle, predicting that isocitrate dehydrogenase (IDH) activity would be altered in PAH, and then demonstrating increased IDH activity not only in cultured hPMVEC expressing mutant BMPR2 but also in the serum of PAH patients. These results suggest that widespread metabolic changes are an important part of PAH pathogenesis, and that simultaneous identification and targeting of the multiple involved pathways may be a more fruitful therapeutic approach than targeting of any one individual pathway.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2045-8932 2045-8940 2045-8940
DOI:	10.4103/2045-8932.97606