Thesis
The role of Inhibitory Kappa B kinase alpha (IKKα) in the regulation of Nuclear factor Kappa B signalling in endothelial cells
- Creator
- Awarding institution
- University of Strathclyde
- Date of award
- 2012
- Thesis identifier
- T13233
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- Atherosclerosis is one of the most common cardiovascular diseases in Western Countries. An important feature of the disease is the initiation of atherosclerotic lesions including monocyte recruitment into the vessel wall (Cominacini et al., 2000). This involves the expression a number of adhesion molecules including E-selectin, ICAM-1 and VCAM-1. In endothelial cells, ICAM-1 and VCAM-1 expression is regulated by a number of defined signalling pathways including the transcription factor Nuclear factor Kappa B (NFκB). NFκB activation is regulated by α and β isoforms of the Inhibitory Kappa B kinases (IKK). Whilst IKKβ regulates the canonical pathway involving phosphorylation and degradation of IκB-α and the translocation of p65 NFκB to the nucleus, accumulated evidence implicates that IKKα regulates p65 dependent gene expressions and plays a distinctive role in non-canonical NFκB pathway by mediating processing of p100 NFκB precursor p100. In this PhD thesis, I have examined the effect of adenoviral (Adv.) mediated IKKα and β blockade or siRNA IKKα on NFκB activation and adhesion molecule expression in endothelial cells. In human umbilical vein endothelial cell, over-expression of Adv. DN-IKKβ attenuated TNF-α induced IκB-α degradation and p65 phosphorylation. In contrast, Adv. DN-IKKα had no inhibitory effect of either responses. Furthermore, either Adv. DN-IKKα or siRNA IKKα reduced TNF-α induced NFκB reporter activity and also p65-dependent expression of the adhesion molecules, ICAM-1 and VCAM-1. Taken together, these findings suggest IKKα may regulate NFκB activity and gene expression without being involved in the up-stream canonical NFκB pathway. Moreover, blocking IKKα but not β inhibited TNF-α induced activation of the non-canonical pathway exemplified by p100 processing and the formation of p52. Novel selective IKKα inhibitors, SU1007 and SU1010, generated in house, were employed in the study to confirm the role of IKKα in endothelial cells. Similarly, both SU compounds did not affect TNF-α induced IκB-α degradation and phosphorylation of p65 but inhibited NFκB reporter activity and ICAM-1 and VCAM-1 expression. In addition, SU 1007 and 1010 also showed an inhibitory effect on the non-canonical pathway by blocking both p100 processing and the expression of p100 itself. These findings indicate IKKα plays a key role in the regulation of the non-canonical NFκB pathway and regulates the canonical NFκB pathway via its nuclear activity. These data IV suggest that IKKα inhibition may be a useful approach for the future treatment of cardiovascular disease.
- Resource Type
- DOI
- Date Created
- 2012
- Former identifier
- 947973
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