METTL3 promotes vascular stability in intracranial aneurysm via m6A-AMPK axis
摘要
Intracranial aneurysm (IA) is a type of cerebrovascular complication that can result in subarachnoid hemorrhage. Published research have evidenced the involvement of METTL3, a critical mRNA m6A methyltransferase, in the generation of various cardiovascular diseases. However, its specific role in regulating IAs remains unclear. Our research demonstrated downregulation of METTL3 in IA patients and a significant positive correlation with AMPK expression. In vascular smooth muscle cells (VSMCs), overexpressing METTL3 led to an upregulation of contractile marker genes (SM-22α & α-SMA), while the expressions of TNF-α, IL-1β, iNOS, IL-6, MMP-9, and MMP-3 were significantly downregulated. This effect was reversed by the use of the AMPK inhibitor Compound C. Therefore, it can be postulated that METTL3 may regulate the phenotypic transformation of VSMCs by mediating the AMPK signaling pathway. Additionally, overexpression of METTL3 can suppress the proliferation and migration of VSMCs and promote cell apoptosis. Conversely, overexpressing METTL3 in this rat IA model resulted in improved vessel morphology, enhanced wall thickness, and elevated expression of genes, SM-22α and α-SMA. However, these beneficial effects were reduced following treatment with Compound C. Furthermore, we observed higher immunofluorescence intensity of the M1 macrophage marker CD68 in IA mice compared to significantly lower levels in rats overexpressing METTL3. These results suggest that AMPK inhibition may be mediated by METTL3, which would limit macrophage infiltration and hence prevent the development of IAs. Our investigation demonstrates that METTL3 can modulate the phenotypic transformation of VSMCs by regulating the AMPK signaling pathway. This regulation results in inhibited migration, cell proliferation, promoted apoptosis, and suppression of macrophage infiltration, thereby impeding the progression of IAs.