{
  "abstract": "Background Congenital Heart Diseases (CHDs) are the most common class of newborn defects and despite their high prevalence, the underlying mechanisms and genes involved are not yet clear. Retinoic acid (RA) is the most active metabolite of Vitamin A and has been identified as an important signalling molecule during vertebrate cardiac development. 1 RA binds to nuclear receptors to regulate transcription. Bioavailability of RA is regulated by the balance between two enzyme classes which synthesise (Retinoic acid dehydrogenases - RALDHs) and metabolise (cytochrome p450 subfamily 26 - CYP26s) RA.2 Both the excess and deficiency of RA produce similar heart defects in the embryo.Material and Methods Two novel Retinoic acid metabolism blocking agents (RAMBAs), C2 and C17, and Talarozole (R115866) which inhibit CYP26 function were used to induce RA excess at 6hpf until 24 and 72hpf. 3 RA signalling inhibition was induced with the similar treatment BMS195614 (Retinoic Acid Receptor α Antagonist (RAA)). Cardiac development was analysed by molecular markers for cardiomyocyte specification, with Fisher’s exact Test used to determine statistical significance.Results All RAMBA-treated embryos show defective cardiac chamber formation and looping, indicating in vivo action of the novel RAMBAs and a role for CYP26 enzymes in zebrafish cardiac development. C17 displays higher potency in affecting cardiac specification than C2. Similar defects were seen in RAA-treated embryos, plus cardiac domain posteriorisation.Conclusion This research has demonstrated for the first time the in vivo effect on cardiac development of two novel RAMBAs, shedding light on RA signalling and metabolism during cardiac development.Reference Roberts C. Regulating retinoic acid availability during development and regeneration: the role of the CYP26 enzymes. Journal of Developmental Biology 2020;8(1). https://doi.org/10.3390/jdb8010006. Roberts C, Ivins S, Cook AC, Baldini A, Scambler PJ. Cyp26 genes a1, b1 and c1 are down-regulated in Tbx1 null mice and inhibition of Cyp26 enzyme function produces a phenocopy of DiGeorge syndrome in the chick. Human Molecular Genetics 2006;15(23):3394–3410. https://doi.org/10.1093/hmg/ddl416. Gomaa MS, Bridgens CE, Illingworth NA, Veal GJ, Redfern CPF, Brancale A, Armstrong JL, Simons C. Novel retinoic acid 4- hydroxylase (CYP26) inhibitors based on a 3-(1H- imidazol- and triazol-1-yl)-2,2- dimethyl-3-(4-(phenylamino)phenyl)propyl scaffold. Bioorganic & Medicinal Chemistry [online] 2012;20(14):4201–4207. https://doi.org/10.1016/j.bmc.2012.05.076",
  "authors": [
    {
      "affiliations": [
        "Imperial College London, London, UK"
      ],
      "name": "Maria Carolina Altomonte"
    },
    {
      "affiliations": [
        "King’s College London, London UK and University College London, London, UK"
      ],
      "name": "Anagha Maria Alex"
    },
    {
      "affiliations": [
        "St George’s, University of London, London, UK"
      ],
      "name": "Dilan Durmus"
    },
    {
      "affiliations": [
        "St George’s, University of London, London, UK"
      ],
      "name": "Catherine Roberts"
    }
  ],
  "title": "P18  Impact of novel RAMBAs on cardiac development",
  "uid": "fcc658f5-5167-5443-904d-005b30373abc"
}