{
  "abstract": "Myocardial infarction (MI) is a leading cause of heart failure compounded by the adult heart’s limited regenerative capacity.1 2 Neovascularisation is required for effective repair, yet mechanisms remain poorly defined. We hypothesized that reactivation of fetal genes in adult coronary endothelial cells (ECs) promotes neovascularisation post-MI.Multi-omics analyses identified Annexin A2 (ANXA2) as enriched in ECs during development and reactivated in adult human and mouse hearts post-MI. Immunofluorescence showed higher ANXA2 in cardiac ECs of MI patients versus controls (n = 7;% ANXA2+CD31+: 77.1± 12.1 vs. 56.9 ± 9.2, P = 0.002). Its fibrinolysis co-regulator, Serpin Family E Member 1 (SERPINE1), was also increased (% SERPINE1+CD31+ = 32.7±11.7 vs. 16.1±7.3, P=0.001). We used zebrafish, a model with conserved cardiovascular genes and strong regenerative capacity, to generate CRISPR/Cas9-mediated knockdown of orthologues anxa2ab. These Crispants had developmental defects, including fewer intersegmental vessels (23.3 ± 3.1 vs. 27.8 ± 1.4), smaller eyes (mm: 0.7 ± 0.16 vs. 0.9 ± 0.07), and shorter body length (mm: 9.8 ± 0.9 vs. 10.8 ± 0.4; P < 0.0001; n≥ 26). Following cardiac laser injury at 3 days post fertilisation, anxa2ab Crispants showed impaired regeneration at 48-hour post injury: fewer ECs (61.7 ± 21.3 vs. 89.0 ± 20.1), cardiomyocytes (56.6 ± 17.0 vs. 83.3 ± 14.1), and smaller ventricular volume (μm³: 6.2e6 ± 2.0e6 vs. 1.0e7 ± 2.6e6; P < 0.0001; n=24). qRT-PCR showed transcriptional changes in targets linked with ANXA2 function, including S100 calcium binding protein A10ab, vascular endothelial growth factor Ab, C-X-C motif chemokine ligand 12b, Notch receptor 1a/3, and poly(A) binding protein cytoplasmic 1ab, but not serpine1.These findings identify ANXA2 as a gene that can be reactivated upon cardiac injury whose defect leads to impaired cardiac repair. Elucidating ANXA2-mediated pathways may reveal targets to enhance neovascularisation and heart regeneration.Reference Jenča D, et al. 2021. Heart failure after myocardial infarction: incidence and predictors. ESC Heart Fail, 8, 222–237POSS, K. D., WILSON, L. G. & KEATING, M. T. 2002. Heart Regeneration in Zebrafish. Science 298:2188–2190. Smart N, et al. De novo cardiomyocytes from within the activated adult heart after injury. Nature 2011;474:640–4.",
  "authors": [
    {
      "affiliations": [
        "Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh"
      ],
      "name": "Michelle NH Tang"
    },
    {
      "affiliations": [
        "Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh"
      ],
      "name": "Ziwen Li"
    },
    {
      "affiliations": [
        "Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh"
      ],
      "name": "Panna Tandon"
    },
    {
      "affiliations": [
        "Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh"
      ],
      "name": "Carl S Tucker"
    },
    {
      "affiliations": [
        "Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh"
      ],
      "name": "Jonathan M Taylor"
    },
    {
      "affiliations": [
        "Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh",
        "Department of Physics, University of Glasgow"
      ],
      "name": "James Minchin"
    },
    {
      "affiliations": [
        "Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh"
      ],
      "name": "Martin A Denvir"
    },
    {
      "affiliations": [
        "Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh"
      ],
      "name": "Andrew H Baker"
    },
    {
      "affiliations": [
        "Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh"
      ],
      "name": "Mairi Brittan"
    }
  ],
  "title": "O1  Reactivating developmental genes to promote neovascularisation and cardiac repair following myocardial infarction",
  "uid": "cd55504a-46c4-5559-b8e2-33a5f7d83bc0"
}