Study of arteriosclerosis in the Adult Health Study population (Part 2. Analysis of the cytokine network regulating differentiation of mesenchymal stem cells in artery)

Summary

Reports regarding therapeutic irradiation of the human head and animal experiments, as well as reports involving mortality and incidence of arteriosclerotic diseases among A-bomb survivors, have suggested that high-dose radiation induces arteriosclerosis, but the mechanism of such induction is unclear. It is difficult to explain the entire picture of the complex clinical condition of arteriosclerosis with the conventional hypothesis that arteriosclerosis is an inflammatory disease. Tissue damage is probably of primary importance in relatively high-dose-radiation-induced arteriosclerotic changes. In this study, therefore, we will consider arteriosclerosis based on the “inflammation-response-to-injury” hypothesis. We hypothesize that diseases related to “artery-bone metabolism-immunity” are abnormalities in differentiation and proliferation of arterial mesenchymal tissue. Thus, we also will measure several multi-functional cytokines in 2,100 Adult Health Study (AHS) subjects (including those exposed at young ages). That cross-sectional study is designed to test our hypothesis that “abnormalities in the cytokine network initiated by tissue damage at the time of radiation exposure induce abnormalities in mesenchymal tissues.” We will obtain measurements of arteriosclerotic markers (augmentation index [AI]; brachial-ankle pulse wave velocity [baPWV]; ankle-brachial index [ABI]; intima-media thickness [IMT]; calcification of aortic arch and/or abdominal aorta) and cytokines (pentraxin [PTX]-3; osteopontin [OPN]; osteoprotegerin [OPG]; receptor activator of nuclear factor [NF]-κB ligand [RANKL]; vascular endothelial growth factor [VEGF]-A; high mobility group box [HMGB]-1; apolipoprotein [Apo]-J, also called clusterin; interleukin [IL]-17), which will be measured once during the four years (two cycles) starting in 2010 that constitute our study period. We also will measure reactive oxygen species (ROS), which act as proliferation signals for mesenchymal stem cells. We will then examine if the “cytokine network” functions to either moderate or mediate the radiation effect upon atherosclerotic cardiovascular outcomes.

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