Mitochondrial metabolism in pulmonary hypertension: beyond mountains there are mountains

Culley, Miranda K.; Chan, Stephen Y.

doi:10.1172/jci120847

Cited by 119 publications

(129 citation statements)

References 185 publications

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“…increased glucose uptake and utilization by glycolysis and the pentose shunt in diseased pASMcs. We began by assessing the uptake and utilization of [1,2,[3][4][5][6][7][8][9][10][11][12][13] C 3 ]glucose in diseased versus control PASMCs. Glucose labeled at carbons 1-3 allows the comparative assessment of glucose metabolism through glycolysis versus the pentose shunt.…”

Section: Resultsmentioning

confidence: 99%

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Stable isotope metabolomics of pulmonary artery smooth muscle and endothelial cells in pulmonary hypertension and with TGF-beta treatment

Hernández-Saavedra

Sanders

Freeman

et al. 2020

Sci Rep

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Altered metabolism in pulmonary artery smooth muscle cells (pASMcs) and endothelial cells (pAecs) contributes to the pathology of pulmonary hypertension (pH), but changes in substrate uptake and how substrates are utilized have not been fully characterized. We hypothesized stable isotope metabolomics would identify increased glucose, glutamine and fatty acid uptake and utilization in human pASMcs and pAecs from pH versus control specimens, and that tGf-β treatment would phenocopy these metabolic changes. We used 13 c-labeled glucose, glutamine or a long-chain fatty acid mixture added to cell culture media, and mass spectrometry-based metabolomics to detect and quantify 13 c-labeled metabolites. We found pH pASMcs had increased glucose uptake and utilization by glycolysis and the pentose shunt, but no changes in glutamine or fatty acid uptake or utilization. Diseased pAecs had increased proximate glycolysis pathway intermediates, less pentose shunt flux, increased anaplerosis from glutamine, and decreased fatty acid β-oxidation. tGf-β treatment increased glycolysis in pASMcs, but did not recapitulate the pAec disease phenotype. in tGf-β-treated pASMcs, glucose, glutamine and fatty acids all contributed carbons to the tcA cycle. in conclusion, pASMcs and pAecs collected from pH subjects have significant changes in metabolite uptake and utilization, partially recapitulated by TGF-β treatment. Changes in cellular metabolism are increasingly recognized as a hallmark of pulmonary hypertension (PH) pathobiology 1-4. Shifts in the uptake of metabolic substrates and how they are utilized downstream enables the disease phenotype of vascular cells in PH, including increased proliferation, apoptosis resistance, hypertrophy and vasoconstriction 3. One critical metabolic shift observed in PH is an increase in glycolysis, which is thought to occur in resident vascular wall cells including pulmonary artery smooth muscle cells (PASMCs), endothelial cells (PAECs) and fibroblasts 5-7. Increased glucose uptake can be demonstrated in vivo by increased uptake of the glucose analog 18 F-fluorodeoxyglucose in the lung parenchyma of PH subjects 6,8. The concept that glycolysis in PH is detrimental has led to investigation of the potential utility of dichloroacetate (DCA), which by blocking pyruvate dehydrogenase kinase causes increased glucose flux into the TCA cycle, and less glycolysis 9. Glutamine uptake and metabolism by PAECs has also been shown to contribute to their disease phenotype 10. However, comprehensive assessment of substrate uptake and how the substrates are utilized by pulmonary vascular cells in PH is lacking. A potential driver of altered cellular metabolism is transforming growth factor β (TGF-β) signaling, which underlies many forms of heritable (through mutations in BMPR2 and other members of the TGF-β signaling superfamily) and idiopathic PAH, and PAH etiologies associated with other conditions such as autoimmune

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Section: Resultsmentioning

confidence: 99%

“…All diseased subjects were clinically diagnosed with idiopathic pulmonary arterial hypertension (IPAH). 1 Calculated using Fick cardiac output. N/A: data not available.…”

Section: Pasmcsmentioning

confidence: 99%

Stable isotope metabolomics of pulmonary artery smooth muscle and endothelial cells in pulmonary hypertension and with TGF-beta treatment

Hernández-Saavedra

Sanders

Freeman

et al. 2020

Sci Rep

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“…Reduction in mitochondrial oxidative phosphorylation in PAH is linked with an increase in mitochondrial fragmentation and a reduction in mitochondrial biomass (Culley & Chan, 2018). Accordingly, we observed an increased mitochondrial fragmentation and reduction in mitochondrial content in ECFCs from IPAH patients compared with healthy controls (…”

Section: Mir-150 and Ptpmt1 Restore Cardiolipin Levels In Sugen/hypoxmentioning

confidence: 64%

“…At the cellular level, the arterial and right ventricular remodelling in PAH is associated with a shift from oxidative phosphorylation to glycolysis (Freund-Michel, Khoyrattee et al, 2014), which increases the availability of non-oxidized lipids, amino-acids and sugars essential for rapid cell proliferation (Paulin & Michelakis, 2014). These changes are accompanied by inhibition of mitochondrial biogenesis, mitochondrial fragmentation, membrane hyperpolarization and altered ROS production (Culley & Chan, 2018, Paulin & Michelakis, 2014.…”

Section: Introductionmentioning

confidence: 99%

Role of endothelial microRNA-150 in pulmonary arterial hypertension

Russomanno

Abdul-Salam

et al. 2020

Preprint

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Endothelial dysfunction contributes to the vascular pathology in pulmonary arterial hypertension (PAH). Circulating levels of endothelial miR-150 are reduced in PAH and act as an independent predictor of patient survival. The role of endothelial miR-150 in vascular dysfunction in PAH is not well understood.Endothelium-targeted miR-150 delivery prevented the disease in Sugen/hypoxia mice, while endothelial knockdown of miR-150 had adverse effects. miR-150 target genes revealed significant associations with PAH pathways, including proliferation, inflammation and phospholipid signaling, with PTEN-like mitochondrial phosphatase (PTPMT1) most markedly altered. PTPMT1 reduced inflammation, apoptosis and improved mitochondrial function in human pulmonary endothelial cells and blood-derived endothelial colony forming cells (ECFCs) from idiopathic PAH. Beneficial effects of miR-150 in vitro and in vivo were linked with PTPMT1-dependent biosynthesis of mitochondrial phospholipid cardiolipin and reduced expression of pro-apoptotic, pro-inflammatory and pro-fibrotic genes, including c-MYB, NOTCH3, TGF-β and Col1a1.In conclusion, we are first to show that miR-150-PTPMT1-cardiolipin pathway attenuates pulmonary endothelial damage induced by vascular stresses and may be considered as a potential therapeutic strategy in PAH.

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“…Our ability to identify and target early derangements in mitochondrial function may provide opportunities for therapeutic interventions in right heart failure. 9…”

mentioning

confidence: 99%