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II参与促进早期血管生成的机制， 损伤、炎症和脂质过氧化，所有这些都参与了 开始动脉粥样硬化形成。这些研究人员假设， 血脂异常激活单核细胞表型部分由 激活骨髓肾素-血管紧张素系统（RAS）。的新颖特征 这种假设是：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; 2） 血脂异常增加骨髓Ang II的产生;和3） 活化的单核细胞表型受增加的Ang II 1型（AT 1）调节 受体表达或活性。在具体目标1中，他们将调查 使用RT-PCR在食蟹猴中表达RAS组分， Western blot;此外，他们将定位细胞中的各种成分。 通过原位杂交和免疫细胞化学的组合， 评估血管紧张素受体的类型发现造血细胞的流动 细胞仪在具体目标2中，他们将通过以下方式确定分子机制： 其高脂蛋白血症增加骨髓RAS活性。他们还将 用流式细胞仪和克隆形成技术检测骨髓细胞表型 在食蟹猴中通过阵列分析测定和鉴定改变的基因表达 给猴子喂食致动脉粥样硬化的食物。在具体目标3中，他们将评估是否 阻断AT 1受体可改变骨髓造血和 在高胆固醇血症食蟹猴中， AT 1受体拮抗剂使用目标2中列出的技术。拟议 研究将揭示动脉粥样硬化的新机制， 对开发适用的新治疗方式产生重大影响 心血管和血管疾病。

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.