The role of histone deacetylase 7 alternative translation in vascular remodelling

A 7 amino acid (7A, MHSPGAD) peptide was found alternatively translated from one of the transcript variants of mouse histone deacetylase 7 (Hdac7) mRNA. In this study, phosphorylated 7A (7Ap, MH[pS]PGAD) was able to increase Sca1+ vascular progenitor cells (VPCs) self-renewal with upregulation of E2F2 and cyclin D1 proteins and also improve angiogenesis in ischemic tissues in in vivo studies. A mutated 7Ap (7Am) was then designed to resist multiple proteases digestion in in vivo studies, retaining 7Ap’s cellular functions on cell migration and cell self-renewal. 7Am was also found to be able to stabilize glucose level in db/db mice model, together with evidence in in vitro studies that 7Ap could increase insulin secretion and glucose transporter 4 expression. Furthermore, 7A/7Ap could interact with HK1 and PKM2 increasing HK1’s activity in glycolysis as well as increasing both HK1 and PKM2 nuclear translocation related to their functions on gene transcription regulation. 7A was also found to possibly involved in protein glycosylation. In order to further understand the function of 7A in vivo, an Hd7-7sFLAG transgenic mice was generated, which could act as 7A knockout mice model, and it was confirmed that endogenous 7A existed. To further validate 7A’s role in vascular remodelling, a femoral artery injury model was introduced in the transgenic mice. Compared to wild type mice, the transgenic mice showed severe retardation of vascular injury repair, which was partially rescued by exogenous 7A supply. The 7A deficiency also abolished angiogenesis in ischemic tissues in a hindlimb ischemia model, leading to complete limb loss and death, which could also be rescued by exogenous 7A supply. Interestingly, 7A deficiency in those transgenic mice resulted in increased body weight gain under normal diet and increased amount of fat tissue, and this was ablated by administration of 7Am in male transgenic mice. We also discovered increased CD45+ cells from Sca1+ VPC population in transgenic mice, and those CD45+/Sca1+ cells may contribute to the body weight gain.