SMYD3-PARP16 axis accelerates unfolded protein response and mediates neointima formation
| Autor: | Gang Wei, Yi-Zhun Zhu, Xinhua Liu, Di Yang, Ting Ni, Fen Long, Jinghua Wang, Qing Wang |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Intimal hyperplasia
medicine.medical_treatment VCAM-1 vascular cell adhesion molecule-1 PDGF platelet-derived growth factor PERK protein kinase R (PKR)-like ER kinase 0302 clinical medicine UPR unfolded protein response PARP poly(ADP-ribose) polymerases BIP immunoglobulin heavy-chain binding protein SMCs smooth muscle cells General Pharmacology Toxicology and Pharmaceutics ChIP-seq chromatin immunoprecipitation coupled with deep sequencing Neointimal hyperplasia 0303 health sciences SMYD3 EGCG epigallocatechin-3-gallate p-eIF2α phosphate-eukaryotic initiation factor 2α biology Chemistry H3K4 histone H3 lysine 4 MMP matrix metal proteinase Cell biology ECM extracellular matrix 030220 oncology & carcinogenesis Vascular smooth muscle cell Original Article VSMCs vascular smooth muscle cells Platelet-derived growth factor receptor Neointima SMYD3 SET and MYND domain containing 3 ATF6 activating transcription factor 6 PCNA proliferating cell nuclear antigen PARP16 IRE1 inositol-requiring enzyme 1 RM1-950 IACUC Institutional Animal Care and Use Committee ER endoplasmic reticulum 03 medical and health sciences medicine 030304 developmental biology Endoplasmic reticulum Growth factor XBP-1 X-box binding protein-1 medicine.disease siRNA small interfering RNA Unfolded protein response biology.protein Therapeutics. Pharmacology Chromatin immunoprecipitation DAPI 4′ 6-diamidino-2-phenylindole p-PERK phosphate-PKR-like ER kinase |
| Zdroj: | Acta Pharmaceutica Sinica. B Acta Pharmaceutica Sinica B, Vol 11, Iss 5, Pp 1261-1273 (2021) |
| ISSN: | 2211-3835 |
| Popis: | 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. Graphical abstract 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.Image 1 |
| Databáze: | OpenAIRE |
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