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

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.