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Paraquat-induced cholesterol biosynthesis proteins dysregulation in human brain microvascular endothelial cells.

ABSTRACT: Despite Paraquat (PQ) being banned in several countries, it is still one of the most commonly used herbicides in agriculture. This compound is known to induce damaging effects on human and animal brain cells by generating Reactive Oxygen Species (ROS). However, there is few evidence of PQ effect on Human Brain Microvascular Endothelial Cells (HBMECs), one of the major component of the Blood-Brain Barrier (BBB). The present study aimed at unraveling biological mechanisms associated to the exposure of 1, 10 and 100 µM of PQ for 24 h on HBMECs. High-throughput mass spectrometry-based proteomics using data-independent acquisition (DIA) was applied. Biological pathway enrichment and cellular assays such as mitochondrial respiration and cholesterol level were performed to verify proteomics results. A total of 3753 proteins were quantified out of which 419 were significantly modulated by paraquat exposure. Biological pathway enrichment revealed the ubiquinone metabolism, a pathway directly linked to mitochondrial complex I proteins, confirming the well-known mechanism of PQ inducing oxidative stress. Additionally, this study also described the cholesterol biosynthesis modulation on HBMECs not yet described. In conclusion, our data indicate the toxic effect of PQ on HBMECs by downregulating proteins involved in mitochondrial complex I and cholesterol pathways.

SUBMITTER: Tatjana V

PROVIDER: S-EPMC8438088 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Proteomics analysis unraveled paraquat-induced cholesterol biosynthesis dysregulation in human brain microvascular endothelial cells

Project description:Despite its banishment in several countries, Paraquat (PQ) is still one of the most commonly used herbicides in agriculture. This compound is known to induce damaging effects on human or animal brain cells such as glial cells or neurons through biological processes as redox by generation of Reactive Oxygen Species (ROS). This specific perturbation has already proven its association for increasing the risk of developing a long-term brain impairment in in vitro and in vivo studies using brain cells. However, there is few evidence of PQ effect on Human Brain Microvascular Endothelial Cells (HBMECs), a particular cell type acting as a macromolecule permeability regulator in the Blood-Brain Barrier (BBB). The present study aimed at unraveling biological mechanisms associated to the exposition of 1, 10 and 100 µM of PQ for 24h on HBMECs. High-throughput mass spectrometry-based proteomics using data-independent acquisition (DIA) was applied. Biological pathway enrichment and cellular assays such as mitochondrial respiration and cholesterol level of PQ-treated HBMECs were performed to verify proteomics results. Proteomic experiment reported a total of 3753 quantified proteins out of which 419 were significantly modulated by paraquat exposure. Biological pathway enrichment revealed that the modified proteins are involved in pathways such as the ubiquinone metabolism, a pathway directly linked to mitochondrial complex I proteins. This study also unveiled the modulation of the cholesterol metabolism. In conclusion, most of the highly differentially expressed proteins (DEPs) in PQ-treated HBMECs were associated to the ubiquinone metabolism pathway confirming the well know mechanism of PQ inducing oxidative stress and inhibit mitochondrial complex I activity. Additionally, this study also described the cholesterol biosynthesis modulation on primary human brain endothelial cells not yet described.

2022-02-17 | PXD026975 | Pride

Protein content of extracellular vesicles from human brain microvascular endothelial cells treated by paraquat

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2021-09-10 | PXD024691 | Pride

Dysregulation of Plasmalogen Homeostasis Impairs Cholesterol Biosynthesis.

Project description:Plasmalogen biosynthesis is regulated by modulating fatty acyl-CoA reductase 1 stability in a manner dependent on cellular plasmalogen level. However, physiological significance of the regulation of plasmalogen biosynthesis remains unknown. Here we show that elevation of the cellular plasmalogen level reduces cholesterol biosynthesis without affecting the isoprenylation of proteins such as Rab and Pex19p. Analysis of intermediate metabolites in cholesterol biosynthesis suggests that the first oxidative step in cholesterol biosynthesis catalyzed by squalene monooxygenase (SQLE), an important regulator downstream HMG-CoA reductase in cholesterol synthesis, is reduced by degradation of SQLE upon elevation of cellular plasmalogen level. By contrast, the defect of plasmalogen synthesis causes elevation of SQLE expression, resulting in the reduction of 2,3-epoxysqualene required for cholesterol synthesis, hence implying a novel physiological consequence of the regulation of plasmalogen biosynthesis.

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Ubiquinone Metabolism and Transcription HIF-1 Targets Pathway Are Toxicity Signature Pathways Present in Extracellular Vesicles of Paraquat-Exposed Human Brain Microvascular Endothelial Cells.

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P120 catenin attenuates lipopolysaccharide-induced blood-brain barrier dysfunction and inflammatory responses in human brain microvascular endothelial cells.

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