Biology subjects

Caruso, P.

Publications and source records attributed to Caruso, P..

3 recordsLinked to original sources

bioRxiv2026

Interrogation of the glycolytic axis in pulmonary arterial hypertension models and how modifying these can lead to potential therapeutic options.

IntroductionPulmonary arterial hypertension (PAH) describes diseases characterized by increased pulmonary vessel pressures that lead to right ventricular failure and death if left untreated. Dysregulated metabolic function has been reported in endothelial cells from PAH patients. Healthy endothelial cells can rapidly shift from quiescence to proliferative and apoptotic states, partly due to a greater utilization of glycolysis for ATP production, rather than the slower oxidative phosphorylation more commonly relied on by other cell types. However, in PAH patients, pulmonary artery endothelial cells demonstrate an even greater shift towards glycolytic ATP production. This phenomenon, which was first described in cancer as the Warburg effect, is an adaptation for optimizing both energy production and biosynthetic processes for maximum proliferative potential. Hypothesis and MethodsWe hypothesize that targeting the PKM2 axis in endothelial cells may shift the balance to favor oxidative phosphorylation, in effect reversing the Warburg effect; and that this would have beneficial effects in cell and rodent models of PAH. To this end we have tested TEPP-46, an allosteric PKM2 activator that stabilizes the tetrameric form, blocking its translocation into the nucleus and increasing canonical enzymatic activity, in blood outgrowth endothelial cells (BOECs) and in a rat Sugen-hypoxia model. ResultsTEPP-46 treatment reduced levels of nuclear PKM2 (the homodimer form which promotes anabolic effects and proliferation). Cytoplasmic levels of PKM2 and levels of PKM1 were unaffected. Exposure to TEPP-46 lowered levels of polypyrimidine tract-binding protein 1 (PTPB1), which controls alternative splicing of the PKM gene to promote PKM2 expression; and reduced LDHA, which converts pyruvate to lactate, preventing its utilization for oxidative phosphorylation. In the Sugen-hypoxia rat model, administration of TEPP-46 significantly ameliorated the elevated right ventricular systolic pressures, reduced the loss of body weight and increased survival. The increased muscularization of the smaller blood arteries and arterioles in the lungs of rats due to Sugen-hypoxia were also improved by concurrent administration of TEPP-46. ConclusionWe have shown that TEPP-46 treatment reduces nuclear PKM2 and represses PKM2-driven gene expression, with the functional effect of ameliorating the Sugen-hypoxia phenotype. This suggests that antagonizing the Warburg effect may offer a novel therapeutic avenue for PAH.

physiology↗

bioRxiv2024

Transcriptomic analysis reveals lipid metabolism and macrophage involvement associated with nintedanib treatment in a rat bleomycin model

INTRODUCTIONIdiopathic pulmonary fibrosis (IPF) is a progressive and irreversible lung disease with a poor prognosis. While pirfenidone and nintedanib offer some benefits, they cannot cure IPF. Nintedanib inhibits various proliferative pathways and has antifibrotic effects, but its molecular mechanisms and impact on the lung transcriptome in vivo remain unclear. This study aims to evaluate nintedanibs transcriptomic profile in a rat model of bleomycin-induced lung fibrosis. METHODOLOGY/PRINCIPAL FINDINGSLung fibrosis was induced by two intratracheal administrations of bleomycin. Nintedanib protocol included three weeks of daily oral treatments beginning seven days after the first bleomycin dose. Left lungs were processed for histological evaluation using an automated fibrosis quantification system and the Ashcroft Score, while the right lungs were used for RNA sequencing to conduct differential expression and correlation network analysis (WGCNA). WGCNA modules were examined by cell and pathway enrichment analysis. Lipid peroxidation was assessed through the measurement of malondialdehyde in right lung lysates. Bleomycin induced significant fibrotic lesions, as confirmed by the histological evaluations. Nintedanib reduced fibrotic lesion size by about 15% and decreased severe Ashcroft scores. When compared to controls, the number of differentially expressed genes decreased from over 2000 to barely more than 400 after nintedanib treatment. WGCNA identified two gene clusters correlated to histological parameters, with nintedanib-treated animals showing gene expression levels similar to control animals. One cluster was associated with mesenchymal cells and extracellular matrix-related pathways, in line with the known anti-fibrotic effect of nintedanib. The second cluster, involving principally macrophages, was related to lipid metabolism, potentially uncovering a new mechanistic role of nintedanib in modulating lung fibrosis. CONCLUSIONS/SIGNIFICANCEThe mechanisms involving macrophages and lipid metabolism, influenced by nintedanib in this study, may open new research directions to better inquire the role of this cellular type in tissue repair and pathological lung fibrosis.

pharmacology and toxicology↗

bioRxiv2020

Circulating BMP9 protects the pulmonary endothelium during inflammation-induced lung injury in mice

RationalePulmonary endothelial permeability contributes to the high-permeability pulmonary edema that characterizes acute respiratory distress syndrome (ARDS), which carries a high mortality. Circulating bone morphogeneic protein 9 (BMP9) is emerging as an important regulator of pulmonary vascular homeostasis. ObjectiveTo determine whether endogenous BMP9 plays a role in preserving pulmonary endothelial integrity, and whether loss of endogenous BMP9 occurs during lipopolysacharride (LPS)-induced lung inflammation and permeability. MethodsA BMP9-neutralizing antibody was administrated to healthy adult mice and lung vasculature was examined. Potential mechanisms were delineated by transcript analysis in human primary lung endothelial cells. Impact of BMP9 was evaluated in a murine acute lung injury model induced by inhaled LPS. Levels of BMP9 were measured in plasma from patients with sepsis and endotoxemic mice. Main ResultsSubacute neutralization of endogenous BMP9 in mice resulted in increased lung vascular permeability, interstitial edema and neutrophil extravasation. In lung endothelial cells, BMP9 regulated a programme of gene expression and pathways controlling vascular permeability and cell membrane integrity. Augmentation of BMP9 signalling in mice with exogenous BMP9 prevented inhaled LPS-caused lung injury and edema. In endotoxemic mice, endogenous BMP9 levels were markedly reduced, due to a transient reduction in hepatic BMP9 mRNA expression and increased elastase activity in plasma. In human sepsis patients, circulating levels of BMP9 were also markedly reduced. ConclusionsEndogenous circulating BMP9 is a pulmonary endothelial protective factor, down-regulated during inflammation. Supplementation with exogenous BMP9 offers a potential therapy to prevent increased pulmonary endothelial permeability in the setting of lung injury. Short summaryO_ST_ABSScientific Knowledge on the SubjectC_ST_ABSIncreased pulmonary endothelial permeability is a major factor in the development of acute respiratory distress syndrome (ARDS). Evidence is emerging that circulating BMP9, secreted from the liver, might protect the pulmonary endothelium from injury. For example, loss of BMP9 levels or signalling receptor contributes to the development of pulmonary arterial hypertension. The role of endogenous BMP9 in endothelial permeability remains unclear. What This Study Adds to the FieldHere we show that subacute neutralization of endogenous BMP9 leads to lung vascular injury, including enhanced permeability and neutrophil extravasation. BMP9 levels were markedly reduced in the setting of inflammation in mice and humans. Conversely, exogenous supplementation of BMP9 protected the lung from LPS-induced injury. This study suggests that exogenous BMP9 could offer a novel approach to prevent increased pulmonary endothelial permeability in the setting of lung injury and ARDS.

physiology↗