Zur Kurzanzeige

The role of STAT1-cooperative DNA binding in myocardial infarction

dc.contributor.advisorMeyer, Thomas Prof. Dr.
dc.contributor.authorDoudin, Asmma
dc.date.accessioned2019-08-09T09:43:04Z
dc.date.available2019-08-09T09:43:04Z
dc.date.issued2019-08-09
dc.identifier.urihttp://hdl.handle.net/21.11130/00-1735-0000-0003-C18D-4
dc.identifier.urihttp://dx.doi.org/10.53846/goediss-7600
dc.language.isoengde
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc610
dc.titleThe role of STAT1-cooperative DNA binding in myocardial infarctionde
dc.typedoctoralThesisde
dc.contributor.refereeIvetic, Aleksandar Dr.
dc.date.examination2019-08-06
dc.description.abstractengMyocardial infarction (MI), defined as heart damage due to prolonged ischemia, accounts for significant mortality and morbidity and has a substantial financial burden worldwide. While major advancements have been achieved in the characterization of the JAK/STAT signalling pathway in the context of stress and infection, numerous questions on its involvement in cardiac dysfunction and remodeling remain unanswered. In this study, ligation of the left anterior descending coronary artery (LAD) was performed in wild-type and knock-in mice expressing a STAT1 point mutant with defective cooperative DNA binding (STAT1-F77A), to address the role of interferon signalling in acute myocardial infarction. We hypothesized that mice with dysfunctional STAT1 signalling would show a similar phenotype to mice expressing hyperactive STAT3 with respect to its cardioprotective actions. Using echocardiographic evaluation and transcriptomic analysis, we found that a loss of STAT1 tetramerisation protected against adverse cardiac remodeling in female mice. RNA sequencing uncovered numerous immune and metabolic pathways that were differentially regulated in these mice at day 1 post-myocardial injury. The top five immune-related pathways that were upregulated post-MI in both wild-type and F77A mice were cytokine-cytokine receptor interactions, chemokine signalling pathways, cell adhesion molecules, regulation of actin cytoskeleton and leukocyte transendothelial migration, whereas the top five metabolism-related pathways downregulated post-MI were oxidative phosphorylation, citrate cycle, fatty acid metabolism, fatty acid degradation, and propanoate metabolism in both wild-type and STAT1-F77A mice. Gene set enrichment analysis revealed a downregulation of cardiac muscle contraction pathway in STAT1-F77A mice only, conceivably due to a heterogeneous cell population of infiltrating immune cells in the infarcted myocardium. In addition, the distinctive transcriptomic profile of infiltrating immune cells in the infarcted area of STAT1-F77A mice was characterized by the upregulation of several immune-activating markers to a higher order of magnitude as compared to their wild-type littermates, including chemokines and their receptors, adhesion molecules, cytokines and their receptors, growth factors and their receptors, coagulation cascade proteins, and heat shock proteins. Notably, the top ten genes differentially expressed in the infarcted area of STAT1-F77A were Fgf23, Cxcl3, Slfn4, Rab44, Cxcl2, Cd177, Gm5483, Il1r2, Cd300lf, and Slfn1. The observed upregulation of genes encoding neutrophil markers and adhesion molecules and the significant downregulation of genes engaged in oxidative phosphorylation in the STAT1-F77A mouse line as compared to wild-type mice may act as an adaptive response to reduce oxidative stress, repair cardiac damage and increase survival. Additionally, in a parallel plate flow chamber assay, STAT1- and STAT3-knockdown HL-60 cells had reduced transendothelial migration when compared to control cells. We conclude that in the early phase of myocardial infarction, a series of transcriptional regulations can probably initiate a beneficial remodeling of the left ventricle in a mouse model expressing dysfunctional STAT1. This study has expanded our understanding of STAT1 transcriptional regulation within the context of murine myocardial infarction.de
dc.contributor.coRefereeLutz, Susanne Prof. Dr.
dc.subject.engSTAT1de
dc.subject.engSterile inflammationde
dc.subject.engMyocardial infarctionde
dc.subject.engRNA-seqde
dc.subject.engCooperative DNA-bindingde
dc.identifier.urnurn:nbn:de:gbv:7-21.11130/00-1735-0000-0003-C18D-4-0
dc.affiliation.instituteMedizinische Fakultät
dc.subject.gokfullMedizin (PPN619874732)de
dc.identifier.ppn1672307341


Dateien

Thumbnail

Das Dokument erscheint in:

Zur Kurzanzeige