Coordinated Control of Vascular SMC Growth & Fibrogeneni

血管平滑肌细胞（SMC）是动脉的主要细胞成分，合成血管壁的大量结缔组织，包括弹性蛋白和I型和V/Xi型纤维状胶原。响应于损伤和某些疾病状态如动脉粥样硬化，正常静止的中膜SMC迁移到内膜，在那里它们经历增殖，并存款基质组分，从而有助于动脉粥样硬化斑块的形成和血管闭塞。更重要的是，越来越多的证据表明，斑块纤维帽的破裂会导致冠状动脉和颈动脉粥样硬化的血栓栓塞并发症 疾病巨细胞病毒（CMV）感染是动脉粥样硬化和再狭窄发病机制中的一个促成因素。PI实验室的工作导致了这样的假设，即myb和NF-κ B家族的转录因子在协调控制血管SMC的基质合成和增殖中起关键作用。发现B-Myb在培养中抑制SMC I型和V型胶原和弹性蛋白基因转录，并且通过细胞周期蛋白A/cdk 2磷酸化解除了α 2（V）胶原启动子的抑制。最近建立了携带B-myb转基因的转基因小鼠模型;发现转基因小鼠的睾丸和分离的SMC与野生型小鼠相比显示弹性蛋白大幅减少，胶原蛋白和赖氨酰氧化酶mRNA表达大幅降低。虽然B-myb基因表达受SMC生长状态的调节，但c-Myb和A-Myb显示促进血管SMC增殖。此外，发现CMV立即早期（IE）1蛋白选择性地诱导RelB/p50 NF-κ B复合物，其可以控制 促进SMC增殖的基因。在这里，提出了四个目的来阐明Myb和NF-κ B因子在心血管疾病中的作用：目的1。确定B-Myb异位表达对股动脉损伤所致病变形成的影响。为了阐明高脂肪饮食的影响，将B-myb转基因小鼠与ApoE敲除小鼠杂交，以将B-Myb过表达置于ApoE -/背景的背景中。将评价B-Myb表达对基质沉积、病变形成和血管壁几何重塑的影响;目的2.阐明转录抑制的机制 弹性蛋白基因表达的B-Myb;目的3.阐明细胞周期蛋白A磷酸化消除B-Myb抑制基质基因表达的能力的机制;目的4。阐明CMV IE 1蛋白激活NF-κ B RelB亚基的机制及其在控制细胞增殖的基因反式激活中的作用。这些研究应提供重要的新信息控制两个关键介质在心血管疾病：血管平滑肌细胞增殖和基质生产。

Vascular smooth muscle cells (SMCs), the major cellular constituent of an artery, synthesize of the bulk of the connective tissue of the vessel wall, including elastin and the fibrillar collagens type I and V/XI. In response to injury and in certain disease states such as atherosclerosis, normally quiescent medial SMCs migrate to the intima where they undergo proliferation, and deposit matrix components, thereby contributing to formation of an atherosclerotic plaque and to vessel occlusion. Importantly, mounting evidence indicates that rupture of the fibrous cap of the plaque leads to thromboembolic complications in atherosclerotic coronary and carotid artery disease. Cytomegalovirus (CMV) infection has been implicated as a contributing agent in the pathogenesis of atherosclerosis, as well as in restenosis. Work in the PI's lab has led to the hypothesis that the myb and NF-kappaB families of transcription factors play key roles in coordinated control of matrix synthesis and proliferation of the vascular SMC. B-Myb was found to repress SMC type I and V collagen and elastin gene transcription in culture and phosphorylation by cyclin A/cdk2 relieved repression of the alpha2(V) collagen promoter. A transgenic mouse model carrying the B-myb transgene was recently created; the aortae and isolated SMCs of the transgenic mice were found to display a large decrease in elastin and substantially reduced collagen and lysyl oxidase mRNA expression compared to wild type mice. While B-myb gene expression is regulated by SMC growth state, c-Myb and A-Myb were shown to promote vascular SMC proliferation. Furthermore, the CMV immediate early (IE) 1 protein was found to selectively induce RelB/p50 NF-kappaB complexes, which may control transcription of genes that promote SMC proliferation. Here, four aims are proposed to elucidate the roles of Myb and NF-kappaB factors in cardiovascular disease: Aim 1. Determine the effects of ectopic expression of B-Myb on lesion formation as a result of femoral artery injury. To elucidate the effects of a high fat diet, the B-myb transgenic mice will be crossbred with an ApoE knockout mouse to place B-Myb overexpression within the context of an ApoE -/ background. The effects of B-Myb expression on matrix deposition, lesion formation, and geometric remodeling of the vessel wall will be evaluated; Aim 2. Elucidate the mechanism of transcriptional repression of elastin gene expression by B-Myb; Aim 3. Elucidate the mechanism whereby cyclin A phosphorylation ablates the ability of B-Myb to repress matrix gene expression; Aim 4. Elucidate the mechanism of NF-kappaB RelB subunit activation by CMV IE1 protein and its role in transactivation of genes that control cell proliferation. These studies should provide important new information on control of two critical mediators in cardiovascular disease: vascular SMC proliferation and matrix production.