z-logo
open-access-imgOpen Access
Dysfunctional BMPR2 signaling drives an abnormal endothelial requirement for glutamine in pulmonary arterial hypertension
Author(s) -
Egnatchik Robert A.,
Brittain Evan L.,
Shah Amy T.,
Fares Wassim H.,
Ford H. James,
Monahan Ken,
Kang Christie J.,
Kocurek Emily G.,
Zhu Shijun,
Luong Thong,
Nguyen Thuy T.,
Hysinger Erik,
Austin Eric D.,
Skala Melissa C.,
Young Jamey D.,
Roberts L. Jackson,
Hemnes Anna R.,
West James,
Fessel Joshua P.
Publication year - 2017
Publication title -
pulmonary circulation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.791
H-Index - 40
ISSN - 2045-8940
DOI - 10.1086/690236
Subject(s) - glutamine , medicine , pulmonary hypertension , endothelium , metabolism , citric acid cycle , biochemistry , lipid peroxidation , endocrinology , oxidative stress , biology , amino acid
Pulmonary arterial hypertension (PAH) is increasingly recognized as a systemic disease driven by alteration in the normal functioning of multiple metabolic pathways affecting all of the major carbon substrates, including amino acids. We found that human pulmonary hypertension patients (WHO Group I, PAH) exhibit systemic and pulmonary‐specific alterations in glutamine metabolism, with the diseased pulmonary vasculature taking up significantly more glutamine than that of controls. Using cell culture models and transgenic mice expressing PAH‐causing BMPR2 mutations, we found that the pulmonary endothelium in PAH shunts significantly more glutamine carbon into the tricarboxylic acid (TCA) cycle than wild‐type endothelium. Increased glutamine metabolism through the TCA cycle is required by the endothelium in PAH to survive, to sustain normal energetics, and to manifest the hyperproliferative phenotype characteristic of disease. The strict requirement for glutamine is driven by loss of sirtuin‐3 (SIRT3) activity through covalent modification by reactive products of lipid peroxidation. Using 2‐hydroxybenzylamine, a scavenger of reactive lipid peroxidation products, we were able to preserve SIRT3 function, to normalize glutamine metabolism, and to prevent the development of PAH in BMPR2 mutant mice. In PAH, targeting glutamine metabolism and the mechanisms that underlie glutamine‐driven metabolic reprogramming represent a viable novel avenue for the development of potentially disease‐modifying therapeutics that could be rapidly translated to human studies.

The content you want is available to Zendy users.

Already have an account? Click here to sign in.
Having issues? You can contact us here