title: Transcriptional response to cardiac injury in the zebrafish: systematic identification of genes with highly concordant activity across in vivo models.
abstract: BACKGROUND
  Zebrafish is a clinically-relevant model of heart regeneration. Unlike mammals, it has a remarkable heart repair capacity after injury, and promises novel translational applications. Amputation and cryoinjury models are key research tools for understanding injury response and regeneration in vivo. An understanding of the transcriptional responses following injury is needed to identify key players of heart tissue repair, as well as potential targets for boosting this property in humans.
  
  
  RESULTS
  We investigated amputation and cryoinjury in vivo models of heart damage in the zebrafish through unbiased, integrative analyses of independent molecular datasets. To detect genes with potential biological roles, we derived computational prediction models with microarray data from heart amputation experiments. We focused on a top-ranked set of genes highly activated in the early post-injury stage, whose activity was further verified in independent microarray datasets. Next, we performed independent validations of expression responses with qPCR in a cryoinjury model. Across in vivo models, the top candidates showed highly concordant responses at 1 and 3 days post-injury, which highlights the predictive power of our analysis strategies and the possible biological relevance of these genes. Top candidates are significantly involved in cell fate specification and differentiation, and include heart failure markers such as periostin, as well as potential new targets for heart regeneration. For example, ptgis and ca2 were overexpressed, while usp2a, a regulator of the p53 pathway, was down-regulated in our in vivo models. Interestingly, a high activity of ptgis and ca2 has been previously observed in failing hearts from rats and humans.
  
  
  CONCLUSIONS
  We identified genes with potential critical roles in the response to cardiac damage in the zebrafish. Their transcriptional activities are reproducible in different in vivo models of cardiac injury.
authors.forename: Sophie
authors.initials: S
authors.lastname: Rodius
authors.forename: Petr V
authors.initials: PV
authors.lastname: Nazarov
authors.forename: Isabel A
authors.initials: IA
authors.lastname: Nepomuceno-Chamorro
authors.forename: Céline
authors.initials: C
authors.lastname: Jeanty
authors.forename: Juan Manuel
authors.initials: JM
authors.lastname: González-Rosa
authors.forename: Mark
authors.initials: M
authors.lastname: Ibberson
authors.forename: Ricardo M Benites
authors.initials: RM
authors.lastname: da Costa
authors.forename: Ioannis
authors.initials: I
authors.lastname: Xenarios
authors.forename: Nadia
authors.initials: N
authors.lastname: Mercader
authors.affiliation: NorLux Neuro-Oncology Laboratory, CRP-Santé, Luxembourg, Luxembourg. francisco.azuaje@crp-sante.lu.
authors.forename: Francisco
authors.initials: F
authors.lastname: Azuaje
mesh_terms: D000818:Animals; D019295:Computational Biology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000502:physiology; D006335:Heart Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D012038:Regeneration; D013997:Time Factors; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins; D003577:Cytochrome P-450 Enzyme System; D010450:Endopeptidases