Determining the role of ZEB1 and ZEB2 in controlling fibroblast activation

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dc.contributor.authorPallikkara Suresh, Rohini
dc.contributor.examiningcommitteeNetticadan, Thomas (Physiology and Pathophysiology)
dc.contributor.examiningcommitteeDhingra, Sanjiv (Physiology and Pathophysiology)
dc.contributor.examiningcommitteeRastegar, Mojgan (Biochemistry and Medical Genetics)
dc.contributor.supervisorWigle, Jeffrey
dc.date.accessioned2025-03-31T17:03:49Z
dc.date.available2025-03-31T17:03:49Z
dc.date.issued2025-03-26
dc.date.submitted2025-03-26T21:38:06Zen_US
dc.date.submitted2025-03-31T16:37:06Zen_US
dc.degree.disciplineBiochemistry and Medical Genetics
dc.degree.levelMaster of Science (M.Sc.)
dc.description.abstractMyocardial infarction (MI) is a leading cause of death in Canada. The activated fibroblast, also known as myofibroblast, is a key player in extracellular matrix production, remodeling, and fibrosis in the heart following a MI. Previous studies in our lab have shown that the transcription factor ZEB2 is expressed in activated cardiac fibroblasts and that the overexpression of ZEB2 upregulates the expression of the myofibroblast markers -SMA, SMemb and ED-A fibronectin. The Zinc finger transcription factor family proteins ZEB1 and ZEB2 have crucial roles in embryonic development, angiogenesis, Epithelial-Mesenchymal transition (EMT), and Endothelial-Mesenchymal transition (EndoMT). This study was focused on determining the role of both ZEB1 and ZEB2 in cardiac fibroblast activation. We compared the protein levels of ZEB1 and ZEB2 in primary adult male and female rat cardiac fibroblast cells during the process of fibroblast activation in vitro. As well, we analyzed the effect of over-expression and knockdown of ZEB1 and ZEB2 in the mouse NIH3T3 embryonic fibroblast cell line. Our results show that both ZEB1 and ZEB2 are expressed in the activated fibroblasts with their expression being highest at 48 hours and then decreasing. We observed that ectopic expression of ZEB2 in both NIH3T3 cells and rat primary cardiac fibroblasts resulted in a corresponding decrease in endogenous ZEB1 expression. Furthermore, siRNA mediated knockdown of ZEB2 resulted in increased ZEB1 expression in cardiac fibroblasts and NIH3T3 cells. Similarly, ZEB1 knockdown resulted in increased ZEB2 expression. This shows that ZEB1 and ZEB2 may form a negative feedback loop to maintain an optimal level of their expression in cardiac fibroblasts. ZEB1 and ZEB2 may directly compensate for the loss of the other transcription factor in fibroblasts. Interestingly, despite these regulatory interactions, the expression of the myofibroblast markers, -smooth muscle actin (SMA) and Embryonic smooth muscle heavy chain (SMemb), remain ZEB1 and ZEB2. This study enhances our understanding of the complex interplay between ZEB1 and ZEB2 in cardiac fibroblast activation and provides new insight into the regulatory mechanism underlying this process. These findings could have significant implications to develop new therapeutic strategies for myocardial infarction and heart failure by targeting ZEB1 and ZEB2 to control fibroblast activation and fibrosis.
dc.description.noteMay 2025
dc.identifier.urihttp://hdl.handle.net/1993/38971
dc.language.isoeng
dc.subjectMyocardial Infarction
dc.titleDetermining the role of ZEB1 and ZEB2 in controlling fibroblast activation
local.subject.manitobano
project.funder.nameNatural Sciences and Engineering Research Council of Canada
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