MOLECULAR MECHANISMS CELL COMMUNICATIONS/ATHEROGENESIS

动脉粥样硬化是美国大部分发病率和死亡率的根本原因， 西方世界，是由于正常的焦点不平衡造成的。 动脉壁的平衡。 虽然代谢合作之间 血管细胞是维持正常动脉所必需的， 关于细胞相互作用的性质或它们是如何 在单核细胞-巨噬细胞的募集过程中受到干扰， 动脉粥样硬化 内皮介导的动脉舒张的失败是 高胆固醇血症中沟通功能障碍的一个突出例子 和动脉粥样硬化。 我们将检验一个假设， 高胆固醇血症中的连接（Gj）通讯负责 抑制动脉粥样硬化形成中血管调节。 直接的细胞-细胞通信经由Gj通信信道发生 小的代谢物和离子可以通过这些通道在细胞质之间传递， 相邻的细胞。 北方印迹和核糖核酸探针 杂交分析表明，血管内皮细胞 组织培养中的平滑肌细胞表达Gj蛋白的mRNA 连接蛋白43（cxn 43）。 在这次竞争性的更新中，我们将调查 血管内皮细胞和平滑肌细胞Gj蛋白的表达 原位和体外作为致动脉粥样硬化过程的函数。 病变 在家兔和狒狒实验性高胆固醇血症期间诱导 动脉以及完全发展的动脉粥样硬化 将探测动脉内膜切除术组织的Gj蛋白转录， 通过原位杂交和免疫细胞化学技术进行翻译。 居民语言表达的时空关系 内皮细胞和平滑肌细胞、浸润性浆细胞和脂质 将研究填充的泡沫细胞作为高胆固醇血症的函数。 在平行的体外研究中，改变脂质环境的影响 将从RNA、蛋白质表达、 和功能通信（染料转移和电耦合）。 的 动脉粥样硬化形成和Gj表达相关变化的影响， 将评价血管细胞的直接电耦合。最近的一 一项新的发现是，人体内充满脂质的巨噬泡沫细胞 动脉粥样硬化病变表达cxn 43的mRNA，而 而他们所得到的却不是。 拟议的研究将描述 与血管细胞和巨噬细胞诱导 cxn 43特别强调细胞因子环境， 细胞内胆固醇的积累，以及转录， 涉及翻译和信号转导机制。 这些研究将解决一个知之甚少的机制， 在组织、细胞和分子水平上的通讯， 动脉粥样硬化

Atherosclerosis, the underlying cause of most morbidity and mortality in the Western world, results from a focal imbalance of the normal equilibria of the artery wall. While metabolic cooperation between vascular cells is essential for the maintenance of normal artery, very little is known about the nature of cellular interactions or how they are disturbed during the recruitment of monocyte-macrophages during atherogenesis. Failure of endothelial-mediated arterial relaxation is a prominent example of communication dysfunction in hypercholesterolemia and atherosclerosis. We will examine the hypothesis that compromised gap junctional (Gj) communication in hypercholesterolemia is responsible for inhibition of vasoregulation in atherogenesis. Direct cell-cell communication occurs via Gj communicating channels through which small metabolites and ions can pass between the cytoplasmic compartments of adjacent cells. Northern blot and riboprobe hybridization analyses have demonstrated that both vascular endothelial and smooth muscle cells in tissue culture express mRNA for the Gj protein connexin 43 (cxn43). In this competing renewal, we will investigate vascular endothelial and smooth muscle cell expression of Gj proteins in situ and in vitro as a function of atherogenic processes. Lesions induced during experimental hypercholesterolemia in rabbit and baboon arteries as well as fully developed atherosclerosis in human endarterectomy tissue will be probed for Gj protein transcription and translation by in situ hybridization and immunocytochemical techniques. The spatial and temporal relationships between expression in resident endothelial and smooth muscle cells, infiltrating plasma cells, and lipid filled foam cells will be studied as a function of hypercholesterolemia. In parallel in vitro studies, the influence of altered lipid environment upon vascular cells will be evaluated in terms of RNA, protein expression and functional communication (dye transfer and electrical coupling). The effects of atherogenesis and associated changes in Gj expression and upon direct electrical coupling of vascular cells will be evaluated . A recent novel finding is that lipid-filled macrophage foam cells in human atherosclerotic lesions express mRNA for cxn43 whereas the monocytes from which they are derived do not. The proposed research will delineate the mechanisms associated with vascular cells and macrophage induction of cxn43 with particular emphasis upon the cytokine environment, the role of intracellular cholesterol accumulation, and the transcriptional, translational and signal transduction mechanisms involved. These studies will address a poorly understood mechanism of vascular cell communication at the tissue, cell and molecular level as a function of atherogenesis.