Emerging evidence implicates the participation of Ang II in the mechanisms that contribute to early vascular injury, inflammation, and lipid peroxidation, all of which are involved in the initiation of atherogenesis. These investigators hypothesize that production of activated monocytic phenotypes by dyslipidemia is mediated in part by activation of a bone marrow renin-angiotensin system (RAS). Novel features of this hypothesis are: 1) the cells of the bone marrow produce renin, angiotensinogen, angiotensin-forming enzymes, and angiotensin receptors; 2) dyslipidemia increases bone marrow Ang II production; and 3) production of activated monocytic phenotypes is regulated by increased Ang II type 1 (AT1) receptor expression or activity.
In Specific Aim 1, they will investigate the expression of the components of the RAS in cynomolgus monkeys using RT-PCR and Western blot; in addition, they will localize the various components in the cell by a combination of in situ hybridization and immunocytochemistry and assess the type of angiotensin receptors found on hematopoietic cells by flow cytometry.
In Specific Aim 2 they will determine the molecular mechanisms by which hyperlipoproteinemia increases bone marrow RAS activity. They will also evaluate the phenotypes of bone marrow cells with flow cytometry and clonogenic assays and identify altered gene expression by array analysis in cynomolgus monkeys fed an atherogenic diet.
In Specific Aim 3 they will evaluate whether blockade of the AT1 receptor alters bone marrow myelopoiesis and expression of the bone marrow RAS in hypercholesterolemic cynomolgus monkeys treated with an AT1 receptor antagonist using the techniques listed in Aim 2. The proposed research will uncover novel mechanisms of atherogenesis that may have significant impact in the development of new therapeutic modalities applicable to cardiovascular and blood vessel diseases.
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