SMYD3—PARP16 axis accelerates unfolded protein response and mediates neointima formation

• 作者: Fen Long Di Yang Jinghua Wang Qing Wang Ting Ni Gang Wei Yizhun Zhu Xinhua Liu
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2021,（5）
• 所属期刊栏目: Original articles
• 页码范围: 1261-1273
• 页数: 13页
• 语种: 英文

摘要

Neointimal hyperplasia after vascular injury is a representative complication of restenosis.Endoplasmic reticulum(ER)stress-induced unfolded protein response(UPR)is involved in the pathogen-esis 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 immunopre-cipitation 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 acti-vation 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 prolif-eration 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.