Modulation of signal transduction pathways relevant tp atherosclerosis by dietary chemopreventive agents
thesisposted on 15.12.2014, 10:32 by Paul Alan Atherfold
The dietary constituents curcumin, resveratrol, epigallocatechin-3-gallate (EGCG), but not indole-3-carbinol (I3C) inhibited the activation of NF-kB in B lymphoblasts and HUVEC. EGCG inhibited NF-kB activation in human umbilical vein endothelial cells (HUVECs) by blocking the activity of IKKa, thus preventing subsequent phosphorylation and degradation of IkBa. In B lymphoblasts inhibition of NF-kB activation by EGCG, appeared to be independent of the effect on IkBa. EGCG also prevented the formation of inducible extracellular and intracellular ROS in B lymphoblasts. EGCG inhibited the growth of B lymphoblasts and HUVEC, which was mediated through a cell cycle arrest and induction of apoptosis. Further analysis of this growth inhibitory effect, identified a number of important cell growth regulators that were a target of EGCG. In HUVEC, EGCG growth inhibition appeared to involve p53, CDK1, cyclin D1, and HMOX-1, but was independent of Pin1 and XIAP. In B lymphoblasts, EGCG growth inhibition appeared to be independent of any significant affect on p53, CDK1, cyclin D1, pin1 and XIAP, but may involve the loss of NF-kB activity or increases in HMOX-1 protein. Treatment with EGCG produced changes in the expression of a number of disease relevant genes including HMOX-1, as detected by microarray analysis. This increase in HMOX-1 mRNA corresponded to an increase in HMOX-1 protein. In B lymphoblasts, further analysis revealed that the increase in HMOX-1 was dependent on the PI3K and p38 pathways. The data obtained facilitate the design of preventive dietary intervention studies in healthy volunteers or groups of at risk patients..