SMYD3-PARP16 axis accelerates unfolded protein response and mediates neointima formation.
Acta Pharm Sin B
; 11(5): 1261-1273, 2021 May.
Article
em En
| MEDLINE
| ID: mdl-34094832
ABSTRACT
Neointimal hyperplasia after vascular injury is a representative complication of restenosis. Endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) is involved in the pathogenesis of vascular intimal hyperplasia. PARP16, a member of the poly(ADP-ribose) polymerases family, is correlated with the nuclear envelope and the ER. Here, we found that PERK and IRE1α are ADP-ribosylated by PARP16, and this might promote proliferation and migration of smooth muscle cells (SMCs) during the platelet-derived growth factor (PDGF)-BB stimulating. Using chromatin immunoprecipitation coupled with deep sequencing (ChIP-seq) analysis, PARP16 was identified as a novel target gene for histone H3 lysine 4 (H3K4) methyltransferase SMYD3, and SMYD3 could bind to the promoter of Parp16 and increased H3K4me3 level to activate its host gene's transcription, which causes UPR activation and SMC proliferation. Moreover, knockdown either of PARP16 or SMYD3 impeded the ER stress and SMC proliferation. On the contrary, overexpression of PARP16 induced ER stress and SMC proliferation and migration. In vivo depletion of PARP16 attenuated injury-induced neointimal hyperplasia by mediating UPR activation and neointimal SMC proliferation. This study identified SMYD3-PARP16 is a novel signal axis in regulating UPR and neointimal hyperplasia, and targeting this axis has implications in preventing neointimal hyperplasia related diseases.
ATF6, activating transcription factor 6; BIP, immunoglobulin heavy-chain binding protein; ChIP-seq, chromatin immunoprecipitation coupled with deep sequencing; DAPI, 4',6-diamidino-2-phenylindole; ECM, extracellular matrix; EGCG, epigallocatechin-3-gallate; ER, endoplasmic reticulum; Endoplasmic reticulum; H3K4, histone H3 lysine 4; IACUC, Institutional Animal Care and Use Committee; IRE1, inositol-requiring enzyme 1; MMP, matrix metal proteinase; Neointimal hyperplasia; PARP, poly(ADP-ribose) polymerases; PARP16; PCNA, proliferating cell nuclear antigen; PDGF, platelet-derived growth factor; PERK, protein kinase R (PKR)-like ER kinase; SMCs, smooth muscle cells; SMYD3; SMYD3, SET and MYND domain containing 3; UPR, unfolded protein response; VCAM-1, vascular cell adhesion molecule-1; VSMCs, vascular smooth muscle cells; Vascular smooth muscle cell; XBP-1, X-box binding protein-1; p-PERK, phosphate-PKR-like ER kinase; p-eIF2α, phosphate-eukaryotic initiation factor 2α; siRNA, small interfering RNA
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Acta Pharm Sin B
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
China