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PCSK9 inhibition ameliorates microplastic-induced endothelial redox imbalance via SIRT6 modulation
Nunzia D'Onofrio1,2, Isabella Donisi1, Vitale Del Vecchio3
1Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via L. De Crecchio 7, 80138, Naples, Italy.
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.
Insights
Microplastics (MPs) harm vascular health by impairing endothelial cells and increasing cardiovascular risk. PCSK9 inhibition shows promise in preventing MP-induced endothelial dysfunction via the PCSK9-SIRT6 pathway.
Area of Science:
- Environmental Health
- Cardiovascular Research
- Cellular Biology
Background:
- Microplastics (MPs) are emerging environmental pollutants linked to increased cardiovascular risk.
- The molecular mechanisms by which MPs affect vascular endothelial cells remain largely unknown.
- This study investigates the impact of MPs on endothelial cell function and redox state.
Purpose of the Study:
- To elucidate the effects of polyethylene (PE) and polyvinyl chloride (PVC) microplastics on human endothelial cells.
- To investigate the role of proprotein convertase subtilisin-kexin type 9 (PCSK9) and sirtuin 6 (SIRT6) in MP-induced endothelial dysfunction.
- To evaluate the therapeutic potential of PCSK9 inhibition in mitigating MP-induced vascular damage.
Main Methods:
- Human endothelial cells (teloHAEC, HUVEC, HCAEC) were exposed to PE and PVC microplastics.
- Cell viability, endothelial function, mitochondrial metabolism, and inflammatory markers were assessed.
- PCSK9 and SIRT6 expression levels were quantified; PCSK9 inhibition was evaluated using evolocumab.
Main Results:
- MPs upregulated inflammatory mediators (MCP-1, VCAM1, ICAM1) and promoted apoptosis and cell cycle arrest.
- MP exposure impaired mitochondrial respiration, increased reactive oxygen species (ROS), downregulated SIRT6, and upregulated PCSK9.
- PCSK9 inhibition with evolocumab ameliorated MP-induced endothelial dysfunction, partly via SIRT6 modulation.
Conclusions:
- Microplastic exposure induces endothelial dysfunction through mechanisms involving PCSK9 and SIRT6.
- PCSK9 inhibition represents a potential therapeutic strategy to counteract the cardiovascular risks associated with microplastic pollution.
- The PCSK9-SIRT6 axis is identified as a novel target for preventing microplastic-induced endothelial damage.
