BACKGROUND

Vascular smooth muscle cells (VSMCs), in response to a myriad of injurious stimuli, switch from a contractile state to a proliferative/migratory state in a process known as phenotypic modulation. Phenotypic modulation of VSMCs contributes to neointima formation and underscores a host of vascular pathologies, including atherosclerosis. In the present study, we investigated the involvement of Suv39h1 (suppressor of variegation 3-9 homolog 1), a lysine methyltransferase, in this process.

METHODS

mice were crossbred to the -Cre mice to generate VSMC-restricted Suv39h1 knockout mice (conditional knockout). Vascular injury was created by carotid artery ligation. Cellular transcriptome was evaluated by RNA sequencing and cleavage under targets and tagmentation with deep sequencing.

RESULTS

Suv39h1 upregulation was observed in animal and cell models of phenotypic modulation. Consistently, Suv39h1 silencing restored expression of contractile genes and attenuated proliferation/migration in VSMCs exposed to PDGF (platelet-derived growth factor)-BB. Importantly, Suv39h1 deletion significantly ameliorated neointima formation in mice in both the carotid artery injury model and the femoral artery injury model. Importantly, a small-molecule Suv39h1 inhibitor F5446 suppressed phenotypic modulation in vitro and mitigated vascular injury in mice. RNA sequencing identified HIC1 (hypermethylated in cancer 1) as a novel target for Suv39h1. HIC1 expression was repressed by Suv39h1 during VSMC phenotypic modulation, whereas HIC1 overexpression antagonized neointima formation in mice. Integrated transcriptomic analysis indicated that HIC1 might regulate VSMC phenotypic modulation by activating Jag1 (Jagged 1) transcription.

CONCLUSIONS

Our data suggest that Suv39h1 is a novel regulator of vascular injury and can be targeted for intervention of restenosis.