Inflammation plays a key role during pathological hypertrophy and heart failure. Whilst the roles of pro-inflammatory cytokines are relatively well understood, little is known about the anti-inflammatory cytokines in the heart. Interleukin-10 (IL-10) is a major anti-inflammatory cytokine that is expressed in the heart and may play a crucial role during cardiac remodelling. IL-10 exerts its function by binding to the IL-10 receptor (IL-10R). The primary aim of the PhD study was to investigate the effects of the ubiquitous ablation of IL-10R1 gene during pressure overload induced hypertrophy and to characterise the downstream pathway regulated by IL-10R1 in the heart following pressure overload. The second aim was to investigate the effects of cell specific ablation of IL-10R1 in both the macrophages and cardiomyocytes during pressure overload induced hypertrophy and to identify the specific site where IL-10R1 regulates hypertrophy in the heart. During this study three mouse lines were used: IL-10R1 global knockout (IL-10R1-/-), IL-10R1 macrophage-specific knockout (IL-10R1mKO) and IL-10R1 cardiomyocyte-specific knockout (IL-10R1cKO).Mice with systemic ablation of IL-10 receptor1 (IL-10R1-/-) displayed a significant increase in hypertrophy following two weeks of transverse aortic constriction (TAC) as indicated by heart weight/tibia length ratio (HW/TL). This was accompanied by a significant increase in cardiomyocyte surface area as well as expression of hypertrophic markers such as brain natriuretic peptide (BNP) and Atrial natriuretic peptide (ANP). The IL-10R1-/- mice also had a significant increase in cardiac fibrosis when compared to the WT TAC littermates. Importantly, ejection fraction (EF) and fractional shortening (FS) were significantly reduced in IL-10R1-/- mice compared with WT littermates following TAC. The STAT3 pathway is known as the major downstream signalling pathway regulated by the IL-10R via the activation of the JAK1/STAT3 pathway.  Western blot analysis showed that activation of the STAT3 signalling pathway was significantly reduced in IL-10R1-/- mice following TAC, indicating the possible involvement of this pathway. Furthermore, expression of STAT3 target genes: suppressor of cytokine signalling (SOCS3), tissue inhibitor of metalloproteinases3 (TIMP-3) and heme oxygenase (HO-1) were downregulated in the IL-10R1-/- mice following TAC. Overall the data obtain from the IL-10R1-/- mice indicate that IL-10R1 signalling plays a protective role in reducing pathological hypertrophy in the heart. Interestingly, IL-10R1mKO mice showed no difference in the hypertrophic response following TAC. Analysis of cardiac function and STAT3 activation also showed no difference between IL-10R1mKO and WT controls. This indicated that the protective effects of IL-10R1 mediated signalling during cardiac pressure overload was unlikely due to the effects in residential macrophages. In contrast, IL-10R1cKO mice displayed an elevated hypertrophic response, reduction of cardiac function and less STAT3 activation after TAC. This phenotype resembled those of IL-10R1 global knockout mice. In conclusion, this PhD study has shown that IL-10R1 mediated signalling in the heart is important in controlling pressure-overload hypertrophy. Using cell-specific knockout mice I have shown that IL-10R signalling in cardiomyocytes and not in macrophages is important in this process. These results will open a new insight in targeting IL-10 receptor in the treatment of myocardial hypertrophy in future.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:697754 |
| Date | January 2016 |
| Creators | Assrafally, Farryah |
| Contributors | Cartwright, Elizabeth ; Oceandy, Delvac ; Muller, Werner |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/modulation-of-pathological-cardiac-hypertrophy-via-the-interleukin10-signalling-in-the-cardiomyocytes(430247dd-1512-4e29-9f7a-288bae85fffd).html |
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