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首页> 外文学位 >Control of vascular smooth muscle cell matrix synthesis and proliferation by B-myb and green tea polyphenol.
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Control of vascular smooth muscle cell matrix synthesis and proliferation by B-myb and green tea polyphenol.

机译：B-myb和绿茶多酚控制血管平滑肌细胞基质合成和增殖。

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Vascular smooth muscle cells (SMCs), the major cellular constituent of the artery, synthesize the bulk of fibrillar collagen in the vessel wall. The transcription factor B-myb has been characterized as a negative regulator of collagen gene expression by vascular SMCs in culture. To analyze B-myb function in vivo, a mouse model was generated with human B-myb cDNA driven by the basal cytomegalovirus promoter. In three transgenic lines, human B-myb was expressed in all tissues tested. Importantly, B-Myb protein expression was elevated in the aorta. A dramatic decrease in elastin mRNA levels and a moderate decrease in α1(I) collagen mRNA was observed, and this was confirmed in vascular SMCs isolated from the transgenic mice. These results suggest that expression of B-myb in vivo leads to a repression of matrix gene expression in aortic SMCs in vivo. Moreover, elastin is identified as a new target of B-Myb. Thus, overexpression of B-myb may have the potential to inhibit cardiovascular fibrosis.; Excessive proliferation of SMCs and subsequent matrix deposition are the hallmarks of atherosclerosis and restenosis. Green tea contains polyphenols (GTPs), which inhibit development of atherosclerotic lesions. The most prevalent GTP, epigallochatechin-3-gallate (EGCG), is known for its anti-proliferative effects. The effects of GTPs on aortic SMC proliferation were examined. Cell count and TUNEL assays showed that treatment with a GTP mixture or purified EGCG at doses of 40–50 μg/ml slowed SMC proliferation, while a higher dose of 80 μg/ml EGCG also induced cell death. Apoptosis occurred mainly in proliferating, subconfluent cultures, and was minimal at higher confluency. Treatment with EGCG induced expression of p53 and its target, the cyclin dependent kinase inhibitor p21. Inhibition of p53 reduced EGCG-mediated apoptosis. The increase in p53 protein in SMCs was due to increased p53 protein stability. In some cell types, NF-κB has been shown to be required for p53 mediated cell death. EGCG induced functional NF-κB (p50/p65) complexes, and inhibition of this activity reduced the extent of cell death. Thus, EGCG arrests proliferation and induces cell death in p53- and NF-κB-dependent fashion. These results provide a mechanism by which GTPs prevent the development of atherosclerosis.
机译：血管的平滑肌细胞（SMCs）是动脉的主要细胞成分，在血管壁上合成了大量的纤维状胶原。转录因子B- myb 已被表征为培养中的血管SMCs对胶原基因表达的负调节剂。为了在体内分析B- myb 功能，在基础巨细胞病毒启动子的驱动下，建立了人B-myb cDNA小鼠模型。在三种转基因品系中，人B- myb 在所有测试的组织中均有表达。重要的是，B-Myb蛋白的表达在主动脉中升高。观察到弹性蛋白mRNA水平显着下降，α1（I）胶原mRNA适度下降，这在从转基因小鼠中分离的血管SMC中得到了证实。这些结果表明体内B- myb 的表达导致体内主动脉SMCs中的基质基因表达受到抑制。此外，弹性蛋白被确定为B-Myb的新靶标。因此，B- myb 的过表达可能具有抑制心血管纤维化的潜力。 SMC的过度增殖和随后的基质沉积是动脉粥样硬化和再狭窄的标志。绿茶中含有多酚（GTP），可抑制动脉粥样硬化病变的发展。最普遍的GTP，epigallochatechin-3-gallate（EGCG），以其抗增殖作用而闻名。检查了GTP对主动脉SMC增殖的影响。细胞计数和TUNEL分析表明，以40–50μg/ ml的剂量使用GTP混合物或纯化的EGCG处理可减缓SMC增殖，而更高剂量的80μg/ ml的EGCG也可诱导细胞死亡。凋亡主要发生在增殖的，亚汇合的培养物中，而在较高的汇合中则很少发生。 EGCG处理可诱导p53及其靶标（细胞周期蛋白依赖性激酶抑制剂 p21 ）的表达。抑制p53可减少EGCG介导的细胞凋亡。 SMC中p53蛋白的增加归因于p53蛋白稳定性的提高。在某些细胞类型中，已显示NF-κB是p53介导的细胞死亡所必需的。 EGCG诱导功能性NF-κB（p50 / p65）复合物，抑制该活性可降低细胞死亡的程度。因此，EGCG以p53和NF-κB依赖性的方式阻止增殖并诱导细胞死亡。这些结果提供了GTP防止动脉粥样硬化发展的机制。

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