Aging Negatively Affects Estrogens-Mediated Effects on Nitric Oxide Bioavailability by Shifting ERα/ERβ Balance in Female Mice
Aging Negatively Affects Estrogens-Mediated Effects on Nitric Oxide Bioavailability by Shifting ERα/ERβ Balance in Female Mice
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DOI：
10.1371/journal.pone.0025335
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发表时间：
2011-09-22
期刊：
影响因子：
3.7
通讯作者：
Dantas, Ana Paula
中科院分区：
文献类型：
--
作者：
Novensa, Laura;Novella, Susana;Dantas, Ana Paula
目的：衰老是绝经后雌激素（E2）缺乏心血管保护作用的主要原因之一。我们的研究旨在确定衰老改变E2对加速衰老（SAM）小鼠模型中一氧化氮（NO）产生的影响的机制。方法和结果：虽然我们没有发现女性SAM倾向的NO产生差异，（SAMP，老化）与SAM抗性相比（SAMR，年轻），无论是通过E2 -2荧光或血浆亚硝酸盐/硝酸盐（NO2/NO3），在这两种情况下，E2治疗增加NO生产SAMR，但没有影响SAMP。这些结果与eNOS蛋白和基因表达的变化相一致。E2可上调SAMR中eNOS的表达，但对SAMP无明显影响。还已知E2通过减少超氧阴离子（O-2（-））对NO的催化作用而增加NO。有趣的是，E2处理降低了年轻雌性的O-2（-）产生，而增加了老年雌性的O-2（-）。此外，我们观察到衰老改变了雌激素受体（ER β/ER α）的表达比例和DNA甲基化水平。增加比例ER β/ER α在老年女性与缺乏雌激素调节NO的生产和逆转其抗氧化作用的促氧化prooxidant profile.Conclusions：在一起，我们的数据表明，老化有不利影响E2介导的好处NO的生物利用度，部分通过影响E2的能力，诱导上调eNOS和减少O-2（-）。这些修饰可能与衰老介导的整体DNA甲基化状态的改变有关，但与ER α基因5 '侧翼区的特异性甲基化无关。
Aims: Aging is among the major causes for the lack of cardiovascular protection by estrogen (E2) during postmenopause. Our study aims to determine the mechanisms whereby aging changes E2 effects on nitric oxide (NO) production in a mouse model of accelerated senescence (SAM).Methods and Results: Although we found no differences on NO production in females SAM prone (SAMP, aged) compared to SAM resistant (SAMR, young), by either DAF-2 fluorescence or plasmatic nitrite/nitrate (NO2/NO3), in both cases, E2 treatment increased NO production in SAMR but had no effect in SAMP. Those results are in agreement with changes of eNOS protein and gene expression. E2 up-regulated eNOS expression in SAMR but not in SAMP. E2 is also known to increase NO by decreasing its catabolism by superoxide anion (O-2(-)). Interestingly, E2 treatment decreased O-2(-) production in young females, while increased O-2(-) in aged ones. Furthermore, we observed that aging changed expression ratio of estrogen receptors (ER beta/ER alpha) and levels of DNA methylation. Increased ratio ER beta/ER alpha in aged females is associated to a lack of estrogen modulation of NO production and with a reversal in its antioxidant effect to a pro-oxidant profile.Conclusions: Together, our data suggest that aging has detrimental effects on E2-mediated benefits on NO bioavailability, partially by affecting the ability of E2 to induce up regulation of eNOS and decrease of O-2(-). These modifications may be associated to aging-mediated modifications on global DNA methylation status, but not to a specific methylation at 5'flanking region of ER alpha gene.