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14 KIAA1109 is Differentially Expressed Post Myocardial Infarction and is Required for Vascular Integrity In Zebrafish
  1. Sara Solaymani-Kohal1,2,
  2. Dr Marta Milo2,
  3. Dr TJA Chico1,2
  1. 1University of Sheffield MRC Centre for Developmental and Biomedical Genetics
  2. 2University of Sheffield NIHR Cardiovascular Biomedical Research Unit

Abstract

Background We aimed to identify differentially expressed genes (DE) in whole blood following myocardial infarction (MI) or unstable angina (UA), and assess these functionally in zebrafish models.

Methods We performed whole blood microarrays comparing the transcriptome of patients with MI with UA at serial timepoints post-admission. We then examined the effect of knocking down one DE gene (KIAA1109) by morpholino antisense and examining the effect on vascular development in zebrafish embryos.

Results KIAA1109, a gene of completely unknown function was significantly down regulated in MI compared with UA 1d post MI, with no difference at later timepoints. Knockdown of KIAA1109 in developing zebrafish showed KIAA1109 morphants developed normally but developed cerebral haemorrhage (control 10% vs 50% morphants p<0.05). Haemorrhage volume was greater in KIAA1109 morphants (control 1.2µm3 vs morphants 11.3µm3 p<0.05). KIAA1109 knockdown decreased endothelial cell (EC) number in the forebrain (control 73±6 vs 47±4 morphants) and hindbrain (control 95±7 vs 53±4 morphants). Incubation with the VEGF inducer GS4012 completely rescued the hemorrhagic phenotype.

We performed a microarray comparing whole embryo RNA from KIAA1109 morphants with control to assess the transcriptional effect of loss of function of KIAA1109. This identified DE genes that were significantly down regulated such as genes involved in the cadherin-signalling pathway and genes involved in the NOTCH pathway.

Conclusion KIAA1109 is down regulated in peripheral blood early after MI. KIAA1109 knockdown induced cerebral bleeding in zebrafish embryos that is rescued by VEGF induction, suggesting KIAA1109 is required for vascular integrity.

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