PM2.5 induces pulmonary microvascular injury in COPD via METTL16-mediated m6A modification

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.