FELLOWSHIP for Wu: The role of angiotensinogen oxidation in atherosclerosis

In circulation, total AGT consists of intact AGT and des(AngI)]AGT. Based on redox state, it can also be devided into oxidized AGT and reduced AGT. Since only intact AGT is able to produce angiotensin peptides and oxidized AGT is a better substrate for renin than reduced AGT, it would be misleading if the RAS activity is evaluated based on total AGT without knowledge of intact AGT versus des(AngI)]AGT and oxidized AGT versus reduced AGT. This study will be the first to determine these different forms of AGT in the context of atherosclerosis, and their changes will be examined between normal diet and high fat diet. Oxidized AGT has increased affinity for renin and thus increased rate of angiotensin generation. However, its relevance in physiology is largely unknown. This study will be the first to investigate whether the oxidative status of AGT has any effect on the development of atherosclerosis, and blood pressure will also be examined in the same mouse model. Taken together, this study will look into more detailed changes in the composition of AGT than total AGT, which seems unaffected under many conditions. The physiological relevance of these previously hidden changes will be examined in the context of experimental atherosclerosis, which will not only add to our knowledge on AGT metabolism/clearance but also provide therapeutic implications.