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

Fen Long; Di Yang; Jinghua Wang; Qing Wang; Ting Ni; Gang Wei; Yizhun Zhu; Xinhua Liu

doi:10.1016/j.apsb.2020.12.010

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

Acta Pharm Sin B. 2021 May;11(5):1261-1273. doi: 10.1016/j.apsb.2020.12.010. Epub 2020 Dec 15.

Authors

Fen Long¹, Di Yang¹, Jinghua Wang¹, Qing Wang¹, Ting Ni², Gang Wei², Yizhun Zhu³, Xinhua Liu¹

Affiliations

¹ Pharmacophenomics Laboratory, Human Phenome Institute, Fudan University, Shanghai 201203, China.
² State Key Laboratory of Genetic Engineering & MOE Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center of Genetics and Development, School of Life Sciences and Shanghai Cancer Center, Fudan University, Shanghai 200438, China.
³ State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, China.

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.

Keywords: 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.