S2-3 BRG1-dependent epigenetic control of vascular smooth muscle cell proliferation by hydrogen sulfide

Abstract

Hydrogen sulfide (H 2 S) can modulate the proliferation of vascular smooth muscle cells. This study was designed to investigate the epigenetic control of vascular smooth muscle cell proliferation in response to H 2 S. Microarray analysis indicated that brahma-related gene 1 ( Brg1 ) and proliferation-related genes including proliferating cell nuclear antigen ( Pcna ), neurotrophin 3 ( Ntf3 ) and platelet-derived growth factor subunit A ( Pdgfα ) were significantly downregulated by H 2 S in endothelin-1-stimulated proliferative vascular smooth muscle cells. Brg1 is the central catalytic subunit of the SWI/SNF apparatus (an ATP-dependent chromatin remodeling complex). Overexpression and knockdown of Brg1 confirmed that Brg1 was crucial for H 2 S-induced inhibition of vascular smooth muscle cell proliferation. A luciferase reporter assay, real-time PCR and Western blotting demonstrated that H 2 S inhibited Brg1 transcription and expression. A DNase I hypersensitivity assay revealed that H 2 S reversed endothelin-1-stimulated Pcna , Ntf3 and Pdgfα chromatin remodeling and vascular smooth muscle cell proliferation. A chromatin immunoprecipitation assay indicated that H 2 S inhibited the recruitment of Brg1 to the Pcna , Ntf3 and Pdgfα promoters. The results of this study indicate that H 2 S inhibits vascular smooth muscle cell proliferation via an epigenetic mechanism involving inhibition of Brg1 transcription and expression, and by reducing recruitment of Brg1 to the Pcna , Ntf3 and Pdgfα promoter regions.