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PCSK9 inhibition ameliorates microplastic-induced endothelial redox imbalance via SIRT6 modulation
Summary
Researchers investigated how polyethylene and PVC microplastics affect vascular endothelial cells and identified underlying molecular mechanisms. The study found that microplastics upregulated inflammatory mediators and a protein called PCSK9 in endothelial cells, disrupting their normal function and redox balance. Inhibiting PCSK9 through a SIRT6-dependent pathway ameliorated the microplastic-induced endothelial damage, suggesting a potential therapeutic target for addressing vascular effects of microplastic exposure.
Abstract Background Microplastics (MPs) have emerged as significant environmental pollutants, posing a threat to ecosystems and humans. The presence of MPs in atherosclerotic plaques, exacerbating cardiovascular risk, has been recently reported. However, the molecular mechanism underlying the effects of MPs on the vascular endothelium are still undefined. In this regard, this study aims to investigate the effects of MPs on endothelial cell function and redox state and the underlying mechanisms. Methods Immortalized human aortic endothelial cells (teloHAEC), human umbilical vein endothelial cells (HUVEC), and human coronary artery endothelial cells (HCAEC) were treated with MPs in the form of polyethylene (PE) and polyvinyl chloride (PVC) alone (70 µg/mL) or combined PE (30 µg/mL) + PVC (30 µg/mL) (PE + PVC) for up to 48 h. The effects of MPs on cell viability were evaluated using CCK-8, and its role in endothelial function was evaluated by flow cytometric analyses, enzyme-linked immunosorbent assays (ELISA), and XF HS Seahorse bioanalyzer. Proprotein convertase subtilisin-kexin type 9 (PCSK9) levels were detected by reverse-transcription quantitative polymerase chain reaction (RT-qPCR) and immunoblotting. Molecular involvement of sirtuin 6 (SIRT6) was investigated through gene silencing. Results Our study demonstrated that PE and PVC, alone or in combination, upregulated inflammatory mediators monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM1), and intercellular adhesion molecule-1 (ICAM1) (p < 0.001), modulated the expression of autophagy markers anti-autophagy related 5 (ATG5) and p62, impaired mitochondrial metabolism by reducing maximal and basal respiration and adenosine triphosphate (ATP) production (p < 0.001), promoted reactive oxygen species (ROS) accumulation (p < 0.001) and cell cycle perturbations (p < 0.01), and increased apoptosis cell death (p < 0.001). These events were accompanied by a downregulation of sirtuin 6 (SIRT6) expression (p < 0.01) and an upregulation of PCSK9, at protein and messenger RNA (mRNA) levels (p < 0.01). Treatment with the PCSK9 inhibitor (iPCSK9) evolocumab ameliorated MP-induced cellular redox state imbalance, mitochondrial metabolism alteration, and SIRT6 downregulated levels (p < 0.01). SIRT6 transient silencing experiments denied the beneficial effects of iPCSK9 treatment, indicating that the pleiotropic functions of iPCSK9 may occur, at least in part, via modulation of SIRT6 and Forkhead box O3 (FOXO3A) expression levels. Conclusions Overall, the results indicate that PCSK9 inhibition via evolocumab exhibits substantial promise in the prevention of MP-induced endothelial dysfunction, suggesting the PCSK9–SIRT6 axis as a new promising pathway to target in preventive strategies for cardiovascular risk caused by plastic pollution.
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PCSK9 inhibition ameliorates microplastic-induced endothelial redox imbalance via SIRT6 modulation
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Additional file 1 of PCSK9 inhibition ameliorates microplastic-induced endothelial redox imbalance via SIRT6 modulation
This is a duplicate supplementary file for the PCSK9-microplastic endothelial study (same as ID 2730) — not a standalone research article.
Additional file 1 of PCSK9 inhibition ameliorates microplastic-induced endothelial redox imbalance via SIRT6 modulation
This entry is supplementary material (raw data files) for a study on how blocking a cholesterol-related protein (PCSK9) can protect blood vessel cells from oxidative damage caused by microplastics — not a standalone research article.
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