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Vascular endothelial dysfunction induced by 3-bromofluoranthene via MAPK-mediated-NFκB pro-inflammatory pathway and
Chien-Ying Lee1,2, Sheng-Wen Wu3,4, Jiann-Jou Yang5
1Department of Pharmacology, School of Medicine, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Rd., Taichung, 402, Taiwan, ROC.
Abstract:
3-Bromofluoranthene (3-BrFlu) is the secondary metabolite of fluoranthene, which is classified as a polycyclic aromatic hydrocarbon, through bromination and exists in the fine particulate matter of air pollutants. Endothelial dysfunction plays a critical role in the pathogenesis of cardiovascular and vascular diseases. Little is known about the molecular mechanism of 3-BrFlu on endothelial dysfunction in vivo and in vitro assay. In the present study, 3-BrFlu included concentration-dependent changes in ectopic angiogenesis of the sub-intestinal vein and dilation of the dorsal aorta in zebrafish. Disruption of vascular endothelial integrity and up-regulation of vascular endothelial permeability were also induced by 3-BrFlu in a concentration-dependent manner through pro-inflammatory responses in vascular endothelial cells, namely, SVEC4-10 cells. Generation of pro-inflammatory mediator PGE2 was induced by 3-BrFlu through COX2 expression. Expression of COX2 and generation of pro-inflammatory cytokines, including TNFα and IL-6, were induced by 3-BrFlu through phosphorylation of NF-κB p65, which was mediated by phosphorylation of MAPK, including p38 MAPK, ERK and JNK. Furthermore, generation of intracellular ROS was induced by 3-BrFlu, which is associated with the down-regulated activities of the antioxidant enzyme (AOE), including SOD and catalase. We also found that 3-BrFlu up-regulated expression of the AOE and HO-1 induced by 3-BrFlu through Nrf-2 expression. However, the 3-BrFlu-induced upregulation of AOE and HO-1 expression could not be revised the responses of vascular endothelial dysfunction. In conclusion, 3-BrFlu is a hazardous substance that results in vascular endothelial dysfunction through the MAPK-mediated-NFκB pro-inflammatory pathway and intracellular ROS generation.
Insights
3-Bromofluoranthene (3-BrFlu), an air pollutant, causes vascular endothelial dysfunction. This occurs via a pro-inflammatory pathway involving MAPK and NF-κB, and increased reactive oxygen species (ROS).
Area of Science:
- Environmental Toxicology
- Cardiovascular Research
- Molecular Biology
Background:
- 3-Bromofluoranthene (3-BrFlu) is a polycyclic aromatic hydrocarbon metabolite found in air pollutants.
- Endothelial dysfunction is a key factor in cardiovascular and vascular diseases.
- The molecular mechanisms of 3-BrFlu's effects on endothelial dysfunction are not well understood.
Purpose of the Study:
- To investigate the in vivo and in vitro molecular mechanisms of 3-Bromofluoranthene (3-BrFlu) on vascular endothelial dysfunction.
- To elucidate the role of inflammatory pathways, reactive oxygen species, and antioxidant responses in 3-BrFlu-induced endothelial damage.
Main Methods:
- Zebrafish models were used to assess in vivo vascular effects like angiogenesis and aortic dilation.
- In vitro studies utilized SVEC4-10 cells to examine vascular endothelial integrity and permeability.
- Molecular analyses included measuring inflammatory mediators (PGE2, TNFα, IL-6), enzyme expression (COX2), signaling pathways (MAPK, NF-κB), reactive oxygen species (ROS), and antioxidant enzymes (SOD, catalase, HO-1, Nrf-2).
Main Results:
- 3-BrFlu induced concentration-dependent ectopic angiogenesis and aortic dilation in zebrafish.
- In vitro, 3-BrFlu disrupted endothelial integrity and increased permeability via pro-inflammatory responses, including COX2 expression and subsequent PGE2 generation.
- 3-BrFlu activated the MAPK-mediated-NFκB pathway, leading to increased TNFα and IL-6, and also induced intracellular ROS generation, down-regulating antioxidant enzymes.
- While Nrf-2 mediated an upregulation of antioxidant enzymes (HO-1), this did not reverse the endothelial dysfunction.
Conclusions:
- 3-Bromofluoranthene (3-BrFlu) is a hazardous air pollutant that induces vascular endothelial dysfunction.
- The mechanism involves the MAPK-mediated-NFκB pro-inflammatory pathway and intracellular ROS generation.
- Upregulation of antioxidant enzymes by 3-BrFlu does not prevent the detrimental effects on vascular endothelium.
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