ATHEROGENESIS AND THE BONE MARROW ANGIOTENSIN SYSTEM

描述(由申请人提供)：新出现的证据表明 血管紧张素转换酶II参与早期血管形成的机制 损伤、炎症和脂质过氧化，所有这些都参与了 动脉粥样硬化的启动。这些调查人员假设， 血脂异常引起的单核细胞表型活化部分是通过 激活骨髓肾素-血管紧张素系统(RAS)。新奇的特点 这个假设是：1)骨髓细胞产生肾素， 血管紧张素原、血管紧张素形成酶和血管紧张素受体； 血脂异常会增加骨髓Ang II的生成；以及3) 激活的单核细胞表型受增加的血管紧张素Ⅱ1型(AT1)的调节 受体的表达或活性。在具体目标1中，他们将调查 逆转录-聚合酶链式反应在食蟹猴体内RAS组分的表达 蛋白质印迹；此外，他们将定位不同的成分 通过原位杂交和免疫细胞化学相结合的方法 用Flow评价造血细胞上发现的血管紧张素受体类型 细胞学。在特定目标2中，他们将通过以下方式确定分子机制 哪种高脂蛋白血症可提高骨髓RAS活性。他们还将 流式细胞术和克隆形成法检测骨髓细胞表型 用芯片分析方法检测和鉴定食蟹鱼基因表达的改变 猴子喂食致动脉粥样硬化的食物。在具体目标3中，他们将评估 阻断AT1受体改变骨髓造血和血管内皮生长因子的表达 安慰剂对高胆固醇血症食蟹猴骨髓RAS的影响 使用目标2中列出的技术的AT1受体拮抗剂。 研究将揭示动脉粥样硬化形成的新机制 对开发适用的新治疗方式产生重大影响 心血管疾病和血管疾病。

DESCRIPTION (provided by applicant): 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.