Cardiovascular disease (CVD) is the collective term for diseases that involve the heart or circulation and CVDs are a major cause of mortality and morbidity worldwide. The aim of thesis was to... Show moreCardiovascular disease (CVD) is the collective term for diseases that involve the heart or circulation and CVDs are a major cause of mortality and morbidity worldwide. The aim of thesis was to investigate the role of inflammation in CVD related cardiac and vascular remodelling, which may lead to potential therapeutic agents. We investigated the therapeutic potential of antibodies directed against phosphorylcholine (PC), an endogenous ligand capable of triggering the innate immune system, which is expressed by apoptotic cells and oxidized LDL, in mouse models for myocardial infarction (MI). We found that treatment with anti-PC antibodies reduces adverse cardiac remodelling after both permanent MI as myocardial ischemia reperfusion (MI-R) injury. Furthermore, we found that treatment with annexin A5 also reduces adverse cardiac remodelling after MI-R injury. Interestingly, both anti-PC as annexin A5 treatment reduced the post MI inflammatory response. Next, we investigated the role of PCAF, an inflammatory related epigenetic factor, in vascular remodelling. We found that PCAF deficiency and treatment with a PCAF inhibitor reduces adverse vascular remodelling. Finally, we investigated the role of microRNAs, small RNA molecules that can affect expression of many different gene simultaneously, in vascular remodelling. We show that inhibition of microRNA-495 reduces adverse vascular remodelling. Show less
The work presented in this thesis has provided new insights into the mechanisms involved in the regulation of innate immune responses in zebrafish embryos. Furthermore, cell-specific transcriptome... Show moreThe work presented in this thesis has provided new insights into the mechanisms involved in the regulation of innate immune responses in zebrafish embryos. Furthermore, cell-specific transcriptome profiling studies identified novel marker genes for distinguishing immune cell types, which is highly useful information to fulfill the demand for new fluorescent reporter lines and lineage-specific antibodies in the zebrafish model. We have shown that Ptpn6, a protein tyrosine phosphatase homolog of human SHP1, functions as a critical negative regulator, required for a properly balanced innate immune response and for controlling infections with bacterial pathogens. In Salmonella typhimurium infection, ptpn6 deficiency caused a general hyperinduction of pro-inflammatory genes, which was contraproductive as it impaired the infection control. In Mycobacterium marinum infection, a more specific effect of ptpn6 deficiency on matrix metalloproteinase gene expression was found as a major underlying cause of increased bacterial burden. We further concluded that Ptpn6 functions as a much stronger negative regulator than infection-inducible miRNAs of the miR-146 family, which may be involved in more subtle fine-tuning of the innate immune response. Knowledge about the distinct roles of Ptpn6 and miR-146 miRNAs has practical applicability in regard to their potential as therapeutic targets for inflammatory diseases and cancer. Show less
