AbstractCardiovascular diseases (CVD) are united in pathology by atherosclerosis; signal transduction is essential in this process for the expression of cell adhesion molecules early in the disease, capturing, tethering and transmigrating monocytes into the sub-endothelial space. The local recruitment of inflammatory cells and release of pro-inflammatory mediators induces endothelial dysfunction, an early functional abnormality in CVD. Plasma cytokines have been used to stratify CVD risk in humans. Studies have shown associations between pro-inflammatory tumour necrosis factor (TNF) and interleukin-6 (IL-6) and adverse cardiovascular events. However, the early pathophysiological signalling responsible for the expression of inflammatory molecules in vascular dysfunction remains poorly defined with limited in vivo studies. The ability to quantify endothelial dysfunction in animal models is limited by the need to cull animals in order to obtain vascular tissue, prohibiting longitudinal studies. The development of an in vivo non-invasive technique in this thesis has allowed the longitudinal assessment of microvascular responses in mouse models of inflammation. Candidate kinases in innate inflammatory signalling were assessed in vivo to better understand their role in endothelial dysfunction. These proteins are either essential in inflammatory homeostasis (A20 binding inhibitor of NF-ĸB-1 and mitogen and stress activated kinase 1/ 2) through negative regulation of inflammation or are fundamental in the cascade for cytokines synthesis (myeloid differentiation primary response gene 88, mitogen activated protein kinase activated-protein kinase 2/ 3). Through genetic alteration these models 19 produced a hyper-inflammatory CVD prone phenotype or one that is cardiovascular protective, respectively. Endothelium-dependent vasodilatation was attenuated in the presence of dyslipidaemia through reduced of nitric oxide (NO), cholesterol feeding induced increased expression of IL-6, IL-1α and TNF-α. Importantly, through abrogation of cytokine signalling, NO was preserved in the presence of dyslipidaemia through reduced cytokine release of IL-6 and IL-1α. This data provides a novel insight into the cellular signalling in inflammation and subsequent cardiovascular health, with a translational potential to effectively enhance the understanding of clinical pathology and inflammatory risk. These pathways offer unique therapeutic avenues for pharmacological intervention to potentially limit CVD in the human population.
|Date of Award||2014|
|Supervisor||Faisel Khan (Supervisor) & Jill Belch (Supervisor)|
- Cardiovascular disease
- Vascular function
Systemic Cytokine Expression and Endothelial Dysfunction: Insights from Innate Immune Models of Protein Phosphorylation
Akbar, N. (Author). 2014
Student thesis: Doctoral Thesis › Doctor of Philosophy