Regulation of signaling pathway, cell cycle, and cell growth in atherosclerosis

随着最近生活方式的变化，由于糖尿病、高脂血症和高血压等血管并发症导致的疾病在日本迅速增加，人们越来越需要研究动脉粥样硬化的形成机制。血管内皮细胞和平滑肌细胞生长和凋亡的失控被认为在动脉粥样硬化的形成中起着重要作用。因此，研究这些细胞在这一过程中的信号转导和细胞周期的调控具有重要的意义，这可能会导致预防方法的发展。我们已经发现了p27CDK抑制剂，它是细胞周期的一个明显的刹车，并表明包括p27在内的CDK抑制剂可能在细胞分化和增殖的调节中发挥重要作用。利用血管内皮细胞，我们已经证明了两种CDK抑制剂p21Cip1和p27Kip1在肿瘤坏死因子-α刺激的细胞凋亡调节中可能具有不同的作用。在有胰岛素存在的情况下，肿瘤坏死因子-a诱导p27，而在没有胰岛素的情况下，肿瘤坏死因子-a降低了p27，诱导了p21。未加胰岛素处理的细胞可更有效地诱导细胞凋亡，因此，p27可能具有抑制作用，而p21可能诱导细胞凋亡。由于内皮细胞的凋亡在动脉粥样硬化改变的形成中起重要作用，CDK抑制剂可用于预防。动脉粥样硬化的进展可能是由巨噬细胞、淋巴细胞、内皮细胞和平滑肌细胞局部表达的细胞因子、趋化因子、黏附分子和细胞外基质组成的恶性循环所致。因此，我们将研究这些分子对内皮细胞凋亡的影响，以寻求预防动脉粥样硬化的途径。

There is an increasing demand to investigate the mechanisms of the formation of atherosclerosis, as diseases due to vascular complications of diabetes, hyperlipidemia and hypertension is rapidly increasing in Japan according to the recent changes in life style. Deregulation of the growth and apoptosis of vascular endotherial cells and smooth muscle cells are believed to play important roles in the formation of atherosclerosis. Therefore, it is important to study the controls of signal transduction and cell cycle of these cells during this process, which may lead to a development of the way of prevention. We have discovered the p27 CDK inhibitor, an apparent brake of the cell cycle, and have shown that CDK inhibitors, including p27, may play important roles in the regulation of cell differentiation and proliferation. Using vascular endotherial cell, we have shown that the two CDK inhibitors, p21Cip1 and p27Kip1, may have different roles in the regulations of apoptosis of the cell by the TNF-a stimuli. In the presence of insulin in the culture medium, TNF-a induced p27, where without insulin, TNF-a decreased p27 and induced p21. Apoptosis was induced more efficiently with the cells untreated with insulin, therefore, it is likely that p27 may have suppressive role, where p21 may induce apoptosis. As apoptosis of the endotherial cells are important in the formation of atherosclerotic changes, CDK inhibitors may be utilized in the prevention. Progression of atherosclerosis may be induced through a vicious cycle composed of a combination of cytokines, chemokines, adhesion molecules and extracellular matrix locally expressed by macrophage, lymphocyte, endotherial cell and smooth muscle cells. Therefore, we will investigate the effect of these molecules on the apoptosis of endotherial cells to seek for the way to prevent atherosclerosis.