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A histone deacetylase 7-derived peptide promotes vascular regeneration via facilitating 14-3-3γ phosphorylation

Research output: Contribution to journalArticle

Junyao Yang, Ana Moraga, Jing Xu, Yue Zhao, Peiyi Luo, Ka Hou Lao, Andriana Margariti, Qiang Zhao, Wei Ding, Gang Wang, Min Zhang, Lei Zheng, Zhongyi Zhang, Yanhua Hu, Wen Wang, Lisong Shen, Alberto Smith, Ajay M Shah, Qian Wang, Lingfang Zeng

Original languageEnglish
Pages (from-to)556-573
Number of pages18
JournalStem Cells
Volume38
Issue number4
Early online date29 Jan 2020
DOIs
Publication statusPublished - Apr 2020

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Abstract

Histone deacetylase 7 (HDAC7) plays a pivotal role in the maintenance of the endothelium integrity. In this study, we demonstrated that the intron-containing Hdac7 mRNA existed in the cytosol and that ribosomes bound to a short open reading frame (sORF) within the 5′ terminal noncoding area of this Hdac7 mRNA in response to vascular endothelial growth factor (VEGF) stimulation in the isolated stem cell antigen-1 positive (Sca1 +) vascular progenitor cells (VPCs). A 7-amino acid (7A) peptide has been demonstrated to be translated from the sORF in Sca1 +-VPCs in vitro and in vivo. The 7A peptide was shown to receive phosphate group from the activated mitogen-activated protein kinase MEKK1 and transfer it to 14-3-3 gamma protein, forming an MEKK1-7A-14-3-3γ signal pathway downstream VEGF. The exogenous synthetic 7A peptide could increase Sca1 +-VPCs cell migration, reendothelialization in the femoral artery injury, and angiogenesis in hind limb ischemia. A Hd7-7sFLAG transgenic mice line was generated as the loss-of-function model, in which the 7A peptide was replaced by a FLAG-tagged scrabbled peptide. Loss of the endogenous 7A impaired Sca1 +-VPCs cell migration, reendothelialization of the injured femoral artery, and angiogenesis in ischemic tissues, which could be partially rescued by the addition of the exogenous 7A/7Ap peptide. This study provides evidence that sORFs can be alternatively translated and the derived peptides may play an important role in physiological processes including vascular remodeling.

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