PARP1 contributes to intimal hyperplasia by regulating METTL3-mediated m6A methylation of TRAIL.

Abstract

Poly (ADP-ribose) polymerase 1 (PARP1) promotes vascular intimal hyperplasia (IH) while contributing to N6-methyladenosine (m6A) methylation regulatory processes. The present study focuses on whether the PARP1 inhibitor PJ34 can improve vascular IH by regulating m6A methylation modification. Mice with femoral artery wire injury-induced IH and platelet-derived growth factor-BB (PDGF-BB)-challenged mouse vascular smooth muscle cells (VSMCs) were utilized in the study. PJ34 treatment significantly alleviated neointimal formation, suppressed VSMC proliferation and phenotypic switching, and reduced global m6A methylation and methyltransferase-like 3 (METTL3) expression in injured arteries. Dot blot, RT-qPCR, western blot, and immunohistochemistry confirmed these changes. In vitro, PJ34 impaired PDGF-BB-stimulated proliferation and migration in VSMCs, effects reversed by METTL3 overexpression but not observed in METTL3-deficient cells. Mechanistically, METTL3 regulated the m6A methylation and stability of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mRNA. PJ34 downregulated TRAIL expression via inhibition of METTL3-mediated m6A modification. TRAIL-knockout mice were resistant to the vascular protective effects of PJ34, highlighting the essential downstream role of TRAIL. Immunohistochemistry confirmed TRAIL localization in the neointima and media. Moreover, TRAIL deficiency did not lead to increased systemic inflammation, as TNF-α, IL-6, and IL-1β levels in plasma remained unchanged. In conclusion, PJ34 mitigates vascular IH by modulating METTL3-mediated TRAIL m6A methylation. This finding provides novel insight into epigenetic therapy for vascular remodeling.