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  • Publication
    High-fibre diet affects gut microbiome and prevents the development of hypoxia-induced pulmonary hypertension
    (University College Dublin. School of Medicine, 2022)
    Pulmonary hypertension due to chronic lung diseases, including chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis, is one of the major causes of death worldwide. This pathology is characterised by structural changes in the pulmonary vasculature and sustained vasoconstriction. Treatment options for pulmonary hypertension are based on the regulation of vascular tone but does not demonstrate high efficacy and new ways for controlling disease are needed. Little is known about the role of the gut microbiota and their metabolites in the development of pulmonary hypertension. Recent studies demonstrated that systemic hypertension can be attenuated by gut microbiota intervention. Gut microbes can promote the development of systemic hypertension and can also be a therapeutic target to reduce blood pressure. The aim of this study was to determine if modification of the gut microbiome using a diet that is rich in soluble fibre could prevent the development of hypoxia-induced pulmonary hypertension. The high-fibre diet decreased adverse pulmonary vascular remodelling and decreased right ventricular systolic pressure in mice exposed to hypoxia. These changes were associated with increased abundance of short chain fatty acid-producing bacteria in the gut. Further analysis showed that soluble fibre consumption affected lung myeloid cell populations that were previously recognised as important players in the pathogenesis of pulmonary hypertension. Untargeted proteomic analysis of the right ventricle and the lungs revealed potential molecular pathways that may be affected by soluble fibre supplementation. In the right ventricle these pathways were associated with cardiac hypertrophic changes and glucose metabolism. Diet-induced alterations in inflammatory pathways and pathways related to vessel remodelling were found in the lungs of experimental mice. These data demonstrate for the first time that a high-fibre diet can act on the gut microbiome in the mouse model of hypoxia-induced pulmonary hypertension and prevent disease progression. Soluble fibre can significantly supress structural vascular remodelling and affect pulmonary immune system similar to previous published studies that were obtained in models mimicking left ventricular and systemic circulation dysfunction. Supplementation with high fibre diet could be considered as a supportive lifestyle modification for patients with pulmonary hypertension or subjects that have a high risk of pulmonary diseases.
  • Publication
    Transcriptomics and proteomics revealed sex differences in human pulmonary microvascular endothelial cells
    Marked sexual dimorphism is displayed in the onset and progression of pulmonary hypertension (PH). Females more commonly develop pulmonary arterial hypertension (PAH), yet females with PAH and other types of PH have better survival than males. Pulmonary microvascular endothelial cells play a crucial role in the pulmonary vascular remodelling and increased pulmonary vascular resistance in PH. Given this background, we hypothesized that there are sex differences in the pulmonary microvascular endothelium basally and in response to hypoxia that are independent of the sex hormone environment. Human pulmonary microvascular endothelial cells (HPMECs) from healthy male and female donors, cultured under physiological shear stress, were analysed using RNA sequencing and label-free quantitative proteomics. Gene set enrichment analysis identified a number of sex different pathways both in normoxia and hypoxia, including pathways that regulate cell proliferation. In vitro, rate of proliferation in female HPMECs was lower than in male HPMECs, a finding that supports the omics results. Interestingly, thrombospondin1, an inhibitor of proliferation, was more highly expressed in female than in male cells. These results demonstrate for the first time important differences between female and male HPMECs that persist in the absence of sex hormone differences and identify novel pathways for further investigation that may contribute to sexual dimorphism in pulmonary hypertensive diseases.
  • Publication
    Shear Stress Markedly Alters the Proteomic Response to Hypoxia in Human Pulmonary Endothelial Cells
    Blood flow produces shear stress that homeostatically regulates the phenotype of pulmonary endothelial cells, exerting antiinflammatory and antithrombotic actions and maintaining normal barrier function. Hypoxia due to diseases, such as chronic obstructive pulmonary disease (COPD), causes vasoconstriction, increased vascular resistance, and pulmonary hypertension. Hypoxia-induced changes in endothelial function play a central role in the development of pulmonary hypertension. However, the interactive effects of hypoxia and shear stress on the pulmonary endothelial phenotype have not been studied. Human pulmonary microvascular endothelial cells were cultured in normoxia or hypoxia while subjected to physiological shear stress or in static conditions. Unbiased proteomics was used to identify hypoxia-induced changes in protein expression. Using publicly available single-cell RNA sequencing datasets, differences in gene expression between the alveolar endothelial cells from COPD and healthy lungs were identified. Sixty proteins were identified whose expression changed in response to hypoxia in conditions of physiological shear stress but not in static conditions. These included proteins that are crucial for endothelial homeostasis (e.g., JAM-A [junctional adhesion molecule A], ERG [ETS transcription factor ERG]) or implicated in pulmonary hypertension (e.g., thrombospondin-1). Fifty-five of these 60 have not been previously implicated in the development of hypoxic lung diseases. mRNA for 5 of the 60 (ERG, MCRIP1 [MAPK regulated corepressor interacting protein 1], EIF4A2 [eukaryotic translation initiation factor 4A2], HSP90AA1 [heat shock protein 90 alpha family class A member 1], and DNAJA1 [DnaJ Hsp40 (heat shock protein family) member A1]) showed similar changes in the alveolar endothelial cells of COPD compared with healthy lungs in females but not in males. These data show that the proteomic responses of the pulmonary microvascular endothelium to hypoxia are significantly altered by shear stress and suggest that these shear-hypoxia interactions are important in the development of hypoxic pulmonary vascular disease.
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