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

根据预定的研究计划，我们利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(E_2)对其增殖有抑制作用。(3)研究了E_2对ERK、JNK和p38通路的非基因组作用：E_2强烈抑制ERK通路，但不影响JNK通路。E_2还可诱导p38蛋白激酶的磷酸化，从而诱导SMC的凋亡。(4)E_2对SMC增殖的抑制作用与细胞凋亡有关。接下来，我们对基因组机制进行了研究。(1)E2通过抑制细胞周期进入S期而抑制SMC的增殖。(2)E_2抑制细胞周期蛋白D_1蛋白和Rb的磷酸化。(3)E_2诱导的SMC增殖抑制需要ER-α。此外，我们还研究了选择性雌激素受体调节剂雷洛昔芬在SMC和乳腺癌细胞增殖中的作用。我们发现雷洛昔芬类雌激素通过降低细胞周期蛋白D1水平和Rb磷酸化(对雌激素具有激动性)抑制SMC的增殖，而抑制雌激素诱导的乳腺癌细胞的增殖(拮抗性)。

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).