Ageing presents as the greatest risk factor for development of cardiovascular disease. Calcium/calmodulin dependent protein kinase IIδ (CaMKIIδ) is well established as playing a fundamental role in normal cardiac function, as well contributing to the pathophysiology of heart disease. A similar role for CaMKIIδ in the vasculature remains elusive. Furthermore, very little is known of whether this enzyme contributes to cardiovascular pathology associated with ageing.Oxidative stress and chronic inflammation are both key features of the ageing process and are underpinned predominantly by the development of vascular endothelial dysfunction. Nuclear Factor kappa B (NF-κB) pro-inflammatory signalling is a key modulator of endothelial dysfunction and in recent years has been shown in the heart to be regulated by CaMKIIδ. The precise mechanisms by which CaMKIIδ exerts these effects on NF-κB signalling remain poorly understood and a comparable link has yet to be recognised between both pathways in the vascular endothelium.This study has used a combination of in vitro and in vivo techniques to focus on (i) identifying a link between CaMKII and NF-κB signalling in vascular endothelial cells, (ii) characterising a chronic inflammatory and stressed phenotype in parallel with cardiovascular dysfunction in aged rats, and (iii) assessing alterations in both CaMKII and NF-κB signalling during ageing. Importantly the study has focused on vascular endothelial cells, providing novel insight into the role of CaMKIIδ in these cells during their dysfunction with ageing.A novel direct interaction between CaMKII and NF-κB signalling has been demonstrated at the level of inhibitory-κB kinase β (IKKβ) using proximity ligation assay (PLA) technology. Aged animals displayed visible signs of both cardiac and vascular dysfunction and this correlated with enhanced inflammation and oxidative stress. Interestingly, both CaMKIIδ and NF-κB signalling were both altered specifically at the level of the endothelium with ageing and therefore may both contribute to endothelial dysfunction.Future work should be performed to investigate the interaction between CaMKIIδ and NF-κB in the endothelium in more detail. By specifically targeting the protein-protein interaction between CaMKII and IKKβ, inflammation associated with endothelial dysfunction may be reduced and restoring the balance in activity of both pathways could also reduce or prevent the progression of other age-related conditions.
|Date of Award||27 Apr 2018|
- University Of Strathclyde
|Sponsors||University of Strathclyde|
|Supervisor||Susan Currie (Supervisor) & Andrew Paul (Supervisor)|