The increased proliferation and migration of vascular smooth muscle cells (VSMCs) after arterial injury contributes greatly to the pathogenesis of neointimal hyperplasia. As a major component of epigenetics, histone methylation plays an important role in several cardiovascular diseases. However, its role in restenosis is still unclear.
Human aortic VSMCs were challenged with PDGF‐BB, and total histones were extracted and analysed by HPLC/MS. For the in vivo study, rats were subjected to wire‐guided common carotid injury.
PDGF‐BB markedly increased the H3K27me3 level, as demonstrated by use of HPLC/MS and confirmed by western blot analysis. Enhancer of zeste homologue 2 (EZH2), the histone H3K27 methyltransferase component of polycomb repressive complex 2, was also up‐regulated by PDGF‐BB in VSMCs, and in the neointimal hyperplasia induced by wire injury of the rat carotid artery. Furthermore, inhibiting H3K27me3 by treatment with 3‐μM UNC1999, an EZH2/1 inhibitor, significantly suppressed PDGF‐BB‐induced VSMC proliferation compared with the PDGF‐BB‐treated group. Consistently, neointimal formation was significantly attenuated by oral or perivascular administration of UNC1999 compared with the sham group. Mechanistically, the increase in H3K27me3 inhibited the transcription of the cyclin‐dependent kinase inhibitor p16 INK4A and thus promoted VSMC proliferation.