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BackgroundThis study aims to expand knowledge of the complex process of myocardial infarction (MI) through the application of a systems-based approach.MethodsWe generated a gene co-expression network from microarray data originating from a mouse model of MI. We characterized it on the basis of connectivity patterns and independent biological information. The potential clinical novelty and relevance of top predictions were assessed in the context of disease classification models. Models were validated using independent gene expression data from mouse and human samples.ResultsThe gene co-expression network consisted of 178 genes and 7298 associations. The network was dissected into statistically and biologically meaningful communities of highly interconnected and co-expressed genes. Among the most significant communities, one was distinctly associated with molecular events underlying heart repair after MI (P < 0.05). Col5a2, a gene previously not specifically linked to MI response but responsible for the classic type of Ehlers-Danlos syndrome, was found to have many and strong co-expression associations within this community (11 connections with ρ > 0.85). To validate the potential clinical application of this discovery, we tested its disease discriminatory capacity on independently generated MI datasets from mice and humans. High classification accuracy and concordance was achieved across these evaluations with areas under the receiving operating characteristic curve above 0.8.ConclusionNetwork-based approaches can enable the discovery of clinically-interesting predictive insights that are accurate and robust. Col5a2 shows predictive potential in MI, and in principle may represent a novel candidate marker for the identification and treatment of ischemic cardiovascular disease.

The zebrafish has the capacity to regenerate its heart after severe injury. While the function of a few genes during this process has been studied, we are far from fully understanding how genes interact to coordinate heart regeneration. To enable systematic insights into this phenomenon, we generated and integrated a dynamic co-expression network of heart regeneration in the zebrafish and linked systems-level properties to the underlying molecular events. Across multiple post-injury time points, the network displays topological attributes of biological relevance. We show that regeneration steps are mediated by modules of transcriptionally coordinated genes, and by genes acting as network hubs. We also established direct associations between hubs and validated drivers of heart regeneration with murine and human orthologs. The resulting models and interactive analysis tools are available at http://infused.vital-it.ch. Using a worked example, we demonstrate the usefulness of this unique open resource for hypothesis generation and in silico screening for genes involved in heart regeneration.

fisetin treatment during the reoxygenation phase to mimic medication following surgery or dissolution of the thrombotic clot-our results are concordant. Our data also suggest that fisetin may have roles beyond cardiac protection, promoting cardiomyocyte proliferation and stimulating cardiomyocyte maturation. Further studies of cyclin-CDK complexes expression, degradation, phosphorylation activity and cellular localization would allow to better understand the effect of fisetin on cell cycle and DNA repair. Summing up, we showed that fisetin protects cardiomyocytes from oxidative damage, and that further research could enable the establishment of protocols for myocardial regeneration. These findings demonstrate the value of fisetin as a candidate drug for the repositioning in MI treatment, by inhibiting ischemic damage following MI and overcoming IRI. Methods Brief protocol descriptions can be found hereunder. Detailed methods are described in the Supplementary Material Supplementary Methods. prediction of candidate drugs for repositioning. Candidate compounds were identified through the integrated matching of zebrafish heart regeneration expression signatures against expression signatures obtained from drug-treated cell lines in the Connectivity Map database (CMap, build 2), which contains more than 7 K expression profiles representing more than 1.3 K compounds 58. Before implementing that procedure, we mapped gene sequences from zebrafish to humans 59 and we developed an algorithm for matching multiple regeneration signatures to CMap drug signatures. Our prediction pipeline provided a statistically-ranked, integrated list of compounds predicted to have positive, pro-regeneration potential (Supplementary Methods). chemicals. Fisetin (3,3′,4′,7-Tetrahydroxyflavone, F4043) was purchased from Sigma-Aldrich (St Louis, MO, USA). Drug was dissolved in DMSO to a stock concentration of 100 mM. The final DMSO concentration in cell culture medium never exceeded 0.1% 60 .

BackgroundZebrafish 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.ResultsWe 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.ConclusionsWe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-852) contains supplementary material, which is available to authorized users.