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Microenvironmental Regulation of Macrophage Transcriptomic and Metabolomic Profiles in Pulmonary Hypertension.

ABSTRACT: The recruitment and subsequent polarization of inflammatory monocytes/macrophages in the perivascular regions of pulmonary arteries is a key feature of pulmonary hypertension (PH). However, the mechanisms driving macrophage polarization within the adventitial microenvironment during PH progression remain unclear. We previously established that reciprocal interactions between fibroblasts and macrophages are essential in driving the activated phenotype of both cell types although the signals involved in these interactions remain undefined. We sought to test the hypothesis that adventitial fibroblasts produce a complex array of metabolites and proteins that coordinately direct metabolomic and transcriptomic re-programming of naïve macrophages to recapitulate the pathophysiologic phenotype observed in PH. Media conditioned by pulmonary artery adventitial fibroblasts isolated from pulmonary hypertensive (PH-CM) or age-matched control (CO-CM) calves were used to activate bone marrow derived macrophages. RNA-Seq and mass spectrometry-based metabolomics analyses were performed. Fibroblast conditioned medium from patients with idiopathic pulmonary arterial hypertension or controls were used to validate transcriptional findings. The microenvironment was targeted in vitro using a fibroblast-macrophage co-culture system and in vivo in a mouse model of hypoxia-induced PH. Both CO-CM and PH-CM actively, yet distinctly regulated macrophage transcriptomic and metabolomic profiles. Network integration revealed coordinated rewiring of pro-inflammatory and pro-remodeling gene regulation in concert with altered mitochondrial and intermediary metabolism in response to PH-CM. Pro-inflammation and metabolism are key regulators of macrophage phenotype in vitro, and are closely related to in vivo flow sorted lung interstitial/perivascular macrophages from hypoxic mice. Metabolic changes are accompanied by increased free NADH levels and increased expression of a metabolic sensor and transcriptional co-repressor, C-terminal binding protein 1 (CtBP1), a mechanism shared with adventitial PH-fibroblasts. Targeting the microenvironment created by both cell types with the CtBP1 inhibitor MTOB, inhibited macrophage pro-inflammatory and metabolic re-programming both in vitro and in vivo. In conclusion, coordinated transcriptional and metabolic reprogramming is a critical mechanism regulating macrophage polarization in response to the complex adventitial microenvironment in PH. Targeting the adventitial microenvironment can return activated macrophages toward quiescence and attenuate pathological remodeling that drives PH progression.

SUBMITTER: Li M

PROVIDER: S-EPMC8044406 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPulmonary arterial hypertension (PAH) is a complex disease characterized by progressive right ventricular (RV) failure leading to significant morbidity and mortality. Investigating metabolic features and pathways associated with RV dilation, mortality, and measures of disease severity can provide insight into molecular mechanisms, identify subphenotypes, and suggest potential therapeutic targets.MethodsWe collected data from a prospective cohort of PAH participants and performed untargeted metabolomic profiling on 1045 metabolites from circulating blood. Analyses were intended to identify metabolomic differences across a range of common metrics in PAH (eg, dilated versus nondilated RV). Partial least squares discriminant analysis was first applied to assess the distinguishability of relevant outcomes. Significantly altered metabolites were then identified using linear regression, and Cox regression models (as appropriate for the specific outcome) with adjustments for age, sex, body mass index, and PAH cause. Models exploring RV maladaptation were further adjusted for pulmonary vascular resistance. Pathway enrichment analysis was performed to identify significantly dysregulated processes.ResultsA total of 117 participants with PAH were included. Partial least squares discriminant analysis showed cluster differentiation between participants with dilated versus nondilated RVs, survivors versus nonsurvivors, and across a range of NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, REVEAL 2.0 composite scores, and 6-minute-walk distances. Polyamine and histidine pathways were associated with differences in RV dilation, mortality, NT-proBNP, REVEAL score, and 6-minute walk distance. Acylcarnitine pathways were associated with NT-proBNP, REVEAL score, and 6-minute walk distance. Sphingomyelin pathways were associated with RV dilation and NT-proBNP after adjustment for pulmonary vascular resistance.ConclusionsDistinct plasma metabolomic profiles are associated with RV dilation, mortality, and measures of disease severity in PAH. Polyamine, histidine, and sphingomyelin metabolic pathways represent promising candidates for identifying patients at high risk for poor outcomes and investigation into their roles as markers or mediators of disease progression and RV adaptation.

Project description:We aimed to characterize the plasma metabolome of chronic thromboembolic pulmonary hypertension patients using a high-throughput unbiased omics approach. We collected fasting plasma from a peripheral vein in 33 operable chronic thromboembolic pulmonary hypertension patients, 31 healthy controls, and 21 idiopathic pulmonary arterial hypertension patients matched for age, gender, and body mass index. Metabolomic analysis was performed using an untargeted approach (Metabolon Inc. Durham, NC). Of the total of 862 metabolites identified, 362 were different in chronic thromboembolic pulmonary hypertension compared to controls: 178 were higher and 184 were lower. Compared to idiopathic pulmonary arterial hypertension, 147 metabolites were different in chronic thromboembolic pulmonary hypertension: 45 were higher and 102 were lower. The plasma metabolome allowed us to distinguish subjects with chronic thromboembolic pulmonary hypertension and healthy controls with a predictive accuracy of 89%, and chronic thromboembolic pulmonary hypertension versus idiopathic pulmonary arterial hypertension with 80% accuracy. Compared to idiopathic pulmonary arterial hypertension and healthy controls, chronic thromboembolic pulmonary hypertension patients had higher fatty acids and glycerol; while acyl cholines and lysophospholipids were lower. Compared to healthy controls, both idiopathic pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension patients had increased acyl carnitines, beta-hydroxybutyrate, amino sugars and modified amino acids and nucleosides. The plasma global metabolomic profile of chronic thromboembolic pulmonary hypertension suggests aberrant lipid metabolism characterized by increased lipolysis, fatty acid oxidation, and ketogenesis, concomitant with reduced acyl choline and phospholipid moieties. Future research should investigate the pathogenetic and therapeutic potential of modulating lipid metabolism in chronic thromboembolic pulmonary hypertension.

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Microenvironmental Regulation of Macrophage Transcriptomic and Metabolomic Profiles in Pulmonary Hypertension.

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