铁影响雌激素替代疗法在绝经早晚期对动脉粥样硬化疗效的差异

The incidence of atherosclerosis increases dramatically in postmenopausal women compared to premenopausal women. It has been demonstrated that receiving hormone （estrogen） replacement therapy (HRT) significantly retards the development of atherosclerosis in women at early stage of menopause. However, HRT promotes atherosclerosis at late stage of menopause. The clinical data reveal that the ratio of ERα/ERβ is lower in women at late stage than that at early stage of menopause, suggesting that the ratio of ERα/ERβ might be a key index to evaluate the effect of estrogen. Our previous study showed that iron treatment decreased the ratio of ERα/ERβ in macrophages derived from a female. With the mouse model of menopause at early or late stage, we found that the ratio of ERα/ERβ was lower in mice at early stage than at late stage and iron accumulation increased the difference of the ratio between the early and late-stage mice and worsened the development of atherosclerosis. Thus, we speculate that iron accumulation induced by the absent of monthly blood loss regulates the ratio of ERα/ERβ. In this study, we will use mouse model of menopause at early and late stages with/without macrophage specific ferroportin 1 (an iron exporter) deletion, which causes iron accumulation in macrophages, to investigate whether and how iron accumulation after menopause leads to the imbalance of ERα/ERβ and further results in the different therapeutic effects of HRT for atherosclerosis in menopause women at early and late stages in vivo and in vitro, respectively. On the basis of this work, iron chelation could be considered in combination with HRT to obtain great therapeutical benefits in the treatment of atherosclerosis.

女性绝经后动脉粥样硬化（AS）发病率急剧上升，绝经早期使用雌激素替代疗法（HRT）可显著改善AS，但晚期使用则会促进AS发展。雌激素主要通过雌激素受体ERα和ERβ发挥效应。临床数据显示，绝经晚期血管ERα/ERβ比值小于早期，ERα/ERβ比值可能是衡量疗效的关键指标。我们前期研究发现铁处理会降低巨噬细胞ERα/ERβ比值；绝经早晚期小鼠模型中，晚期血管ERα/ERβ较小，铁累积加剧ERα/ERβ比值差异，加重AS发生发展，推测绝经即周期性失血停止造成的铁累积可能调节ERa/ERβ的比值。本课题以雌激素在绝经早晚期对AS进程的影响为研究对象，以巨噬细胞铁累积小鼠为工具，利用体内外实验及临床样本多个层面研究铁代谢如何调控ERα和ERβ相对表达量，及铁累积影响HRT疗效差异的机制。基于我们的研究，临床上可采用干预铁代谢并与HRT联合使用，以期获得较好的抗AS效果，临床意义重大。

女性绝经后动脉粥样硬化（AS）发病率急剧上升，绝经早期使用雌激素替代疗法（HRT）可显著改善AS，但晚期使用则会促进AS发展。雌激素主要通过雌激素受体ERα和ERβ发挥效应。我们前期研究发现铁处理会降低巨噬细胞ERα/ERβ比值；绝经后机体铁水平显著增加，从而影响雌激素受体相对表达量。临床颈动脉狭窄患者数据显示，随着年龄的增长，斑块和血清中的铁蛋白和铁水平均显著升高，绝经晚期组斑块ERα表达低于早期组。且斑块中ERa与铁蛋白水平呈负相关。绝经早晚期小鼠模型中，晚期血管ERα/ERβ较小，铁累积加剧ERα/ERβ比值差异，绝经晚期给予E2并不能改善反而加重AS，给予DFP抑制铁过载可部分恢复ERα水平，减轻AS。我们还应用了巨噬细胞铁过载模型鼠，即ApoE-/-Fpn1LysM/LysM双敲鼠，我们发现单纯的铁过载也可以引起ERα的表达下降，这一发现可能可以解释绝经晚期雌激素替代疗法失效甚至加重动脉粥样硬化的现象。最后，我们揭示了铁通过E3泛素连接酶MDM2影响雌激素受体表达。基于我们的研究，临床上可采用干预铁代谢并与HRT联合使用，以期获得较好的抗AS效果，临床意义重大。