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Antiatherogenic action of estrogen through inhibition of pathological proliferation in vascular smooth muscle sells

雌激素通过抑制血管平滑肌病理性增殖发挥抗动脉粥样硬化作用

基本信息

批准号：
14370523
负责人：
KURACHI Hirohisa
金额：
$ 8.45万
依托单位：
Yamagata University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

According to the scheduled research program, we obtained the results using human and the primary culture of rat vascular smooth muscle cells (SMC). (1)SMC expresses both estrogen receptor (ER) α and β. (2)SMC proliferates in the presence of high concentrations of serum and platelet-derived growth factor, and estrogen (E2) inhibited the proliferation. (3)Three kinds of MAP kinase family of ERK, JNK and p38 pathways, were investigated for the non-genomic action by E2: E2 strongly suppressed the ERK pathway but it did not affect the JNK. E2 also induced the phosphorylation of p38 MAP kinase which induced apoptosis in SMC. (4)The apoptosis was involved in the inhibition of SMC proliferation by E2. Next, we investigated the genomic mechanism. (1)E2 reduced the proliferation of SMC by inhibiting the progression of cell cycle into S phase. (2)E2 suppressed the amount of cyclin D 1 protein and Rb phosphorylation. (3)ERα was required for the E2-induced inhibition of SMC proliferation. Furthermore, we studied the role of raloxifene, a selective estrogen receptor modulator, in the proliferation of SMC and mammary carcinoma cells. We found that raloxifene like estrogen, inhibited the SMC proliferation by reducing the cyclin D1 level and Rb phosphorylation (agonistic to estrogen), whereas it inhibited the estrogen-induced cell proliferation in mammary carcinoma cells (antagonistic).

根据预定的研究计划，我们采用人和大鼠血管平滑肌细胞（SMC）的原代培养获得了结果。（1）SMC同时表达雌激素受体（ER）α和β。（2）SMC在高浓度血清和血小板衍生生长因子存在下增殖，雌激素（E2）抑制SMC增殖。（3）研究了E2对三种MAP激酶家族的ERK、JNK和p38途径的非基因组作用：E2强烈抑制ERK途径，但对JNK不产生影响。E2还可诱导SMC中p38 MAP激酶磷酸化，从而诱导SMC凋亡。（4）细胞凋亡参与了E2对SMC增殖的抑制作用。接下来，我们研究了基因组机制。(1)E2通过抑制细胞周期进入S期而抑制SMC的增殖。(2)E2抑制细胞周期蛋白D1的表达和Rb的磷酸化。(3)ERα是E2抑制SMC增殖所必需的。此外，我们研究了雷洛昔芬，一种选择性雌激素受体调节剂，在SMC和乳腺癌细胞增殖的作用。我们发现雷洛昔芬像雌激素一样，通过降低细胞周期蛋白D1水平和Rb磷酸化来抑制SMC增殖（对雌激素具有激动作用），而它抑制雌激素诱导的乳腺癌细胞增殖（拮抗作用）。