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

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

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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 non-coding 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 hindlimb ischemia. An 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. © AlphaMed Press 2019 SIGNIFICANCE STATEMENT: Histone deacetylase 7 (HDAC7) plays a pivotal role in the maintenance of the endothelial integrity. Short open reading frames (sORFs) exist within the 5' terminal non-coding area of Hdac7 mRNA. It remains unclear whether these sORFs contribute to HADC7 functions. In this study, we demonstrated that a 7-amino acid peptide could be translated from a sORF. This peptide could act as phosphate group carrier, forming a novel signal transduction pathway, the MEKK1-7A-14-3-3? pathway, downstream VEGF. The novel signal pathway may be involved in vessel wall resident stem/progenitor cell activation and vascular remodeling.

Original languageEnglish
JournalStem Cells
Early online date13 Nov 2019
DOIs
Publication statusEarly online date - 13 Nov 2019

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© 2019 AlphaMed Press.

Cite this

Yang, J., Moraga, A., Xu, J., Zhao, Y., Luo, P., Lao, K. H., Margariti, A., Zhao, Q., Ding, W., Wang, G., Zhang, M., Zheng, L., Zhang, Z., Hu, Y., Wang, W., Shen, L., Smith, A., Shah, A. M., Wang, Q., & Zeng, L. (2019). A histone deacetylase 7-derived peptide promotes vascular regeneration via facilitating 14-3-3γ phosphorylation. Stem Cells. https://doi.org/10.1002/stem.3122