Abstract
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.
Highlights
Alterations in the normal metabolic strategies utilized by various cell types are increasingly recognized as part of a central pathogenic mechanism in pulmonary arterial hypertension (PAH).[1,2] Any given cell type—endothelium, smooth
We found that circulating glutamine levels were significantly elevated in both heritable PAH patients (451 Æ 68 umol/L) and in bone morphogenic protein receptor type 2 (BMPR2) mutation carriers (450 Æ 50 umol/L) compared to controls (399 Æ 82 umol/L, P < 0.05, Fig. 1a)
SIRT3 and hypoxiainducible factor 1-alpha (HIF1a) are two of the best established ‘‘master regulator’’ pathways for cellular metabolism generally and glutamine metabolism. We show that this process can be interrupted in vivo by treating with an orally bioavailable scavenger of isoketals—2HOBA—and that interruption of the molecular cascade leading to glutamine addiction prevents the development of PAH
Summary
Alterations in the normal metabolic strategies utilized by various cell types are increasingly recognized as part of a central pathogenic mechanism in pulmonary arterial hypertension (PAH).[1,2] Any given cell type—endothelium, smooth. It is increasingly recognized that fatty acid metabolism is markedly altered in PAH and that the reciprocal relationship between glucose and fatty acid oxidation (the so-called ‘‘Randle cycle’’) is abnormal in PAH and likely contributes to pathogenesis in both the heart and in the pulmonary vasculature.[8,9,10,11,12,13] The third major cellular carbon source—amino acids generally, and glutamine —remains relatively understudied in PAH.[14] Though amino acids represent the third major carbon source used by most cells, amino acid trafficking has mainly been studied in PAH in the context of nitric oxide synthesis. We hypothesized that the pulmonary endothelium in PAH would exhibit an abnormal increase in glutamine metabolism as a primary carbon source, in a manner similar to what has been observed in cancer
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
