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PM2.5 induces pulmonary microvascular injury in COPD via METTL16-mediated m6A modification
Xiaolan Guo1, Yuyin Lin1, Yingnan Lin1
1Guangzhou Medical University-Guangzhou Institute of Biomedicine and Health (GMU-GIBH) Joint School of Life Sciences, Center for Reproductive Medicine, Key Laboratory for Reproductive Medicine of Guangdong Province, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510000, China.
Abstract:
Fine particulate matter (PM2.5) exposure is a significant cause of chronic obstructive pulmonary disease (COPD), but the detailed mechanisms involved in COPD remain unclear. In this study, we established PM2.5-induced COPD rat models and showed that PM2.5 induced pulmonary microvascular injury via accelerating vascular endothelial apoptosis, increasing vascular permeability, and reducing angiogenesis, thereby contributing to COPD development. Moreover, microvascular injury in COPD was validated by measurements of plasma endothelial microparticles (EMPs) and serum VEGF in COPD patients. We then performed m6A sequencing, which confirmed that altered N6-methyladenosine (m6A) modification was induced by PM2.5 exposure. The results of a series of experiments demonstrated that the expression of methyltransferase-like protein 16 (METTL16), an m6A regulator, was upregulated in PM2.5-induced COPD rats, while the expression of other regulators did not differ upon PM2.5-induction. To clarify the regulatory effect of METTL16-mediated m6A modification induced by PM2.5 on pulmonary microvascular injury, cell apoptosis, permeability, and tube formation, the m6A level in METTL16-knockdown pulmonary microvascular endothelial cells (PMVECs) was evaluated, and the target genes of METTL16 were identified from a set of the differentially expressed and m6A-methylated genes associated with vascular injury and containing predicted sites of METTL16 methylation. The results showed that Sulfatase 2 (Sulf2) and Cytohesin-1 (Cyth1) containing the predicted METTL16 methylation sites, exhibited higher m6A methylation and were downregulated after PM2.5 exposure. Further studies demonstrated that METTL16 may regulate Sulf2 expression via m6A modification and thereby contribute to PM2.5-induced microvascular injury. These findings not only provide a better understanding of the role played by m6A modification in PM2.5-induced microvascular injury, but also identify a new therapeutic target for COPD.
Insights
Fine particulate matter (PM2.5) exposure causes chronic obstructive pulmonary disease (COPD) by damaging lung microvasculature. METTL16-mediated m6A modification of Sulf2 is a key mechanism contributing to this injury.
Area of Science:
- Environmental Health Sciences
- Molecular Biology
- Pulmonary Medicine
Background:
- Fine particulate matter (PM2.5) is a known contributor to chronic obstructive pulmonary disease (COPD).
- The precise molecular mechanisms linking PM2.5 exposure to COPD pathogenesis, particularly concerning pulmonary microvascular injury, remain incompletely understood.
Purpose of the Study:
- To elucidate the mechanisms by which PM2.5 induces pulmonary microvascular injury in the context of COPD.
- To investigate the role of N6-methyladenosine (m6A) modification, specifically involving the regulator METTL16, in PM2.5-induced vascular damage.
Main Methods:
- Establishment of PM2.5-induced COPD rat models.
- Assessment of pulmonary microvascular injury markers (endothelial apoptosis, vascular permeability, angiogenesis, plasma EMPs, serum VEGF).
- m6A sequencing to identify global methylation changes.
- Analysis of METTL16 expression and its functional impact on pulmonary microvascular endothelial cells (PMVECs) using knockdown approaches.
- Identification and validation of METTL16 target genes, such as Sulfatase 2 (Sulf2).
Main Results:
- PM2.5 exposure induced pulmonary microvascular injury in rats, characterized by increased endothelial apoptosis, permeability, and reduced angiogenesis.
- m6A sequencing revealed altered m6A modification patterns following PM2.5 exposure.
- METTL16 expression was upregulated in PM2.5-induced COPD rats; METTL16 knockdown in PMVECs affected apoptosis, permeability, and tube formation.
- METTL16 was found to mediate the m6A methylation and downregulation of Sulfatase 2 (Sulf2), contributing to PM2.5-induced microvascular injury.
Conclusions:
- PM2.5 exposure triggers pulmonary microvascular injury through mechanisms involving altered m6A modification.
- METTL16-mediated m6A modification of Sulf2 is a critical pathway contributing to PM2.5-induced vascular damage in COPD.
- These findings highlight m6A modification and METTL16 as potential therapeutic targets for COPD management.
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