Research Paper Volume 12, Issue 21 pp 21423—21445

Smyd3-PARP16 axis accelerates unfolded protein response and vascular aging

Di Yang1,2,3, , Qing Wang1, , Gang Wei4, , Jiaxue Wu5, , Yi Chun Zhu3, , Qing Zhu6, , Ting Ni4, , Xinhua Liu1, , Yi Zhun Zhu1,2,3, ,

  • 1 Department of Pharmacology, Human Phenome Institute, School of Pharmacy, Fudan University, Shanghai, P.R. China
  • 2 State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, P.R. China
  • 3 Shanghai Key Laboratory of Bioactive Small Molecules and Research Center on Aging and Medicine, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, P.R. China
  • 4 State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center of Genetics and Development, Human Phenome Institute, School of Life Sciences and Huashan Hospital, Fudan University, Shanghai, P.R. China
  • 5 State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, P.R. China
  • 6 School of Pharmacy, Nantong University, Nantong, P.R. China

Received: February 25, 2020       Accepted: July 20, 2020       Published: November 3, 2020
How to Cite

Copyright: © 2020 Yang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Vascular endothelial cell senescence and endoplasmic reticulum (ER) stress induced unfolded protein response (UPR) are two critical contributors to individual aging. However, whether these two biological events have crosstalk and are controlled by shared upstream regulators are largely unknown. Here, we found PARP16, a member of the Poly (ADP-ribose) polymerases family that tail-anchored ER transmembrane, was upregulated in angiotensin II (Ang II)-induced vascular aging and promoted UPR. Further, PARP16 was epigenetically upregulated by Smyd3, a histone H3 lysine 4 methyltransferase that bound to the promotor region of Parp16 gene and increased H3K4me3 level to activate its host gene’s transcription. Intervention of either Smyd3 or PARP16 ameliorated vascular aging associated phenotypes in both cell and mice models. This study identified Smyd3-PARP16 as a novel signal axis in regulating UPR and endothelial senescence, and targeting this axis has implications in preventing vascular aging and related diseases.


ATF6: activating transcription factor 6; ChIP-PCR: Chromatin immunoprecipitation PCR; ChIP-seq: Chromatin Immunoprecipitation coupled with deep sequencing; ER: Endoplasmic reticulum; H3K4: histone H3 at lysine 4; IRE1: inositol-requiring enzyme 1; PERK: protein kinase R [PKR]-like ER kinase; RAECs: Rat Aorta Endothelial Cells; UPR: unfolded protein responses; VSMCs: Rat Vascular Smooth Muscle Cells; VCAM-1: vascular cell adhesion molecule-1.