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, re‐endothelialization 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, re‐endothelialization 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.
Highlights
We demonstrated that the intron-containing Hdac[7] messenger RNA (mRNA) existed in the cytosol and that ribosomes bound to a short open reading frame within the 50-terminal noncoding area of this Hdac[7] mRNA in response to vascular endothelial growth factor (VEGF) stimulation in the isolated stem cell antigen-1 positive (Sca1+) vascular progenitor cells (VPCs)
There were slightly less CD31+ cells in KO mice (Figure 2C). These results indicate that the endogenous 7-amino acid (7A) peptide may participate in Sca1+-VPC activation and affect its contribution to angiogenesis in ischemic tissue; the exogenous 7A peptide may have therapeutic potential in the treatment of angiogenesis-related diseases
Recent studies indicate that one mRNA molecule can encode several peptides through different strategies including multiple ORFs or non-AUG codon-initiated translation, ribosomal frame shifting, stop codon read through, and termination-dependent reinitiation.[28,29,30,31]
Summary
Endothelial injury is a key event in the development of cardiovascular diseases, whereas the regeneration of damaged endothelium is essential for the protection against such diseases.[1,2] Growth factors and the activation of local stem/progenitor cells capable to differentiate toward endothelial cells play a pivotal role in this process.[3,4] Vascular progenitor cells (VPCs), which are mainly located in the adventitia, contribute to the repair of the injured endothelium via migration toward the endothelium and differentiation into the endothelial cell (EC) lineage.[5,6]. We demonstrated that a sORF within a mouse Hdac[7] transcript variant could be translated, giving rise to a 7-amino-acid (7-aa) peptide (7A). This peptide could act as a signal transducer through transferring a phosphate group between a kinase and a substrate; this action modulated stem cell antigen-1-positive VPC (Sca1+-VPC) activation and its effects on vascular injury repair and angiogenesis in ischemic tissues
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