Nakamura Yasuhiro, Suzuki Takashi, Miki Yasuhiro, Tazawa Chika, Senzaki Kumiko, Moriya Takuya, Saito Haruo, Ishibashi Tadashi, Takahashi Shoki, Yamada Shogo, Sasano Hironobu
Department of Pathology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
Mol Cell Endocrinol. 2004 Apr 30;219(1-2):17-26. doi: 10.1016/j.mce.2004.02.013.
Estrogen has been postulated to exert direct anti-atherogenic effects via binding to estrogen receptors (ERs) in vascular smooth muscle cells (VSMCs). Therefore, we believe it is important to examine the status of ER expression in the human cardiovascular system and its disorders. In this study, we first evaluated the relative abundance of messenger RNA (mRNA) of both ER subtypes (ERalpha and ERbeta) in the human aorta using reverse transcription followed by quantitative polymerase chain reaction (RT-qPCR). We then examined the immunolocalization of both ERs in VSMCs of human atherosclerotic lesions. In order to examine which ER subtype was associated with the anti-atherogenic effects of estrogen, we examined the effects of estrogen in two VSMC cell lines, one positive only for ERalpha and the other positive only for ERbeta. The relative abundance of mRNAs for both ERs was higher in female aorta with a mild degree of atherosclerosis than in female aorta with a severe degree of atherosclerosis (P < 0.05). In addition, the number of ERalpha and/or ERbeta double positive cells in the neointima was higher in female aorta with a mild degree of atherosclerosis than in female aorta with severe atherosclerosis (P < 0.05). Our in vitro study found that estradiol was able to significantly inhibit the proliferation of ERalpha positive VSMCs but not ERbeta positive VSMCs (P < 0.05). Moreover, estradiol was found to significantly suppress proliferating cell nuclear antigen (PCNA) mRNA levels in ERalpha positive VSMCs compared to that of ERbeta positive VSMCs, consistent with the findings of cell proliferation. Results from this study suggest that estrogens can inhibit the proliferation of VSMCs through ERalpha, especially in pre-menopausal women. Our study also indicates that decreased levels of ER, especially ERalpha, in the female atherosclerotic neointima may be associated with progression of atherosclerotic changes.
雌激素被认为可通过与血管平滑肌细胞（VSMC）中的雌激素受体（ER）结合发挥直接的抗动脉粥样硬化作用。因此，我们认为研究人类心血管系统及其疾病中ER表达状态很重要。在本研究中，我们首先使用逆转录随后进行定量聚合酶链反应（RT-qPCR）评估了人类主动脉中两种ER亚型（ERα和ERβ）信使RNA（mRNA）的相对丰度。然后我们检测了两种ER在人类动脉粥样硬化病变VSMC中的免疫定位。为了研究哪种ER亚型与雌激素的抗动脉粥样硬化作用相关，我们检测了雌激素对两种VSMC细胞系的作用，一种仅ERα呈阳性，另一种仅ERβ呈阳性。与严重动脉粥样硬化的女性主动脉相比，轻度动脉粥样硬化的女性主动脉中两种ER的mRNA相对丰度更高（P < 0.05）。此外，轻度动脉粥样硬化的女性主动脉新生内膜中ERα和/或ERβ双阳性细胞的数量高于严重动脉粥样硬化的女性主动脉（P < 0.05）。我们的体外研究发现，雌二醇能够显著抑制ERα阳性VSMC的增殖，但不能抑制ERβ阳性VSMC的增殖（P < 0.05）。此外，与ERβ阳性VSMC相比，发现雌二醇能显著抑制ERα阳性VSMC中增殖细胞核抗原（PCNA）的mRNA水平，这与细胞增殖的结果一致。本研究结果表明，雌激素可通过ERα抑制VSMC的增殖，尤其是在绝经前女性中。我们的研究还表明，女性动脉粥样硬化新生内膜中ER水平降低，尤其是ERα水平降低，可能与动脉粥样硬化病变的进展有关。
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