Thesis

The role of Inhibitory Kappa B kinase alpha (IKK?) in the regulation of Nuclear factor Kappa B signalling in endothelial cells

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Awarding institution
  • University of Strathclyde
Date of award
  • 2012
Thesis identifier
  • T13233
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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 (NF?B). NF?B activation is regulated by ? and ? isoforms of the Inhibitory Kappa B kinases (IKK). Whilst IKK? regulates the canonical pathway involving phosphorylation and degradation of I?B-? and the translocation of p65 NF?B to the nucleus, accumulated evidence implicates that IKK? regulates p65 dependent gene expressions and plays a distinctive role in non-canonical NF?B pathway by mediating processing of p100 NF?B precursor p100. In this PhD thesis, I have examined the effect of adenoviral (Adv.) mediated IKK? and ? blockade or siRNA IKK? on NF?B activation and adhesion molecule expression in endothelial cells. In human umbilical vein endothelial cell, over-expression of Adv. DN-IKK? attenuated TNF-? induced I?B-? degradation and p65 phosphorylation. In contrast, Adv. DN-IKK? had no inhibitory effect of either responses. Furthermore, either Adv. DN-IKK? or siRNA IKK? reduced TNF-? induced NF?B reporter activity and also p65-dependent expression of the adhesion molecules, ICAM-1 and VCAM-1. Taken together, these findings suggest IKK? may regulate NF?B activity and gene expression without being involved in the up-stream canonical NF?B pathway. Moreover, blocking IKK? but not ? inhibited TNF-? induced activation of the non-canonical pathway exemplified by p100 processing and the formation of p52. Novel selective IKK? inhibitors, SU1007 and SU1010, generated in house, were employed in the study to confirm the role of IKK? in endothelial cells. Similarly, both SU compounds did not affect TNF-? induced I?B-? degradation and phosphorylation of p65 but inhibited NF?B 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 IKK? plays a key role in the regulation of the non-canonical NF?B pathway and regulates the canonical NF?B pathway via its nuclear activity. These data IV suggest that IKK? inhibition may be a useful approach for the future treatment of cardiovascular disease.
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DOI
Date Created
  • 2012
Former identifier
  • 947973

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