Protective regulation of the ACE2/ACE gene expression by estrogen in human atrial tissue from elderly men
Protective regulation of the ACE2/ACE gene expression by estrogen in human atrial tissue from elderly men
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DOI：
10.1177/1535370217718808
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发表时间：
2017-08-01
影响因子：
3.2
通讯作者：
Goette, A.
中科院分区：
文献类型：
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作者：
Bukowska, A.;Spiller, L.;Goette, A.
动物实验和临床研究的数据表明，性激素显著影响肾素-血管紧张素系统的组分。然而，雌激素是否影响人类心房肌尚未调查。在这项研究中，我们确定了雌激素对心房肾素-血管紧张素系统的关键成分的影响：血管紧张素转换酶，负责生成血管紧张素II和血管紧张素转换酶2，抵消大多数血管紧张素II的影响，以及不同的肾素-血管紧张素系统受体，AT 1 R，AT 2 R和MAS。首先，在从接受心脏手术的患者获得的右心房附件中测定雌激素受体mRNA的表达水平。雌激素受体和雌激素受体β mRNA的量在女性（n = 14）和男性（n = 10）之间相似。从雄性供体制备心房组织切片（350 μ m），所述供体分别暴露于雌激素（1- 100 nM; n = 21）或在存在或不存在100 nM雌激素的情况下以4 Hz刺激24小时（n = 16）。雌激素的给药不会改变雌激素受体的mRNA水平，但会激活MAP激酶Erk 1/2。雌激素使血管紧张素转换酶2-mRNA表达量增加（1.89 ± 0.23; P < 0.05），而使血管紧张素转换酶-mRNA表达量减少（0.78 ± 0.07，P < 0.05）。此外，AT 2 R和MAS的转录水平被雌激素上调。起搏的组织切片显着增加血管紧张素转换酶/血管紧张素转换酶2的比例在mRNA和蛋白质水平。在起搏期间，给予雌激素显著降低了转录物（0.92 +/- 0.21 vs. 2.12 +/- 0.27，4 Hz）和蛋白质水平（0.94 +/- 0.20 vs. 2.14 +/- 0.3，4 Hz）的血管紧张素转换酶/血管紧张素转换酶2比值。此外，雌激素引起的抗炎和抗氧化作用的肾素-血管紧张素系统相关的下游效应，如促氧化LOX-1和促炎ICAM-1。雌激素受体拮抗剂可显著逆转雌激素的抗炎和抗氧化作用。总的来说，我们的研究结果表明，雌激素改变了局部的肾素-血管紧张素系统的稳态，并实现了对老年男性心房肌的保护作用。
Data from animal experiments and clinical investigations suggest that components of the renin-angiotensin system are markedly affected by sex hormones. However, whether estrogen affects human atrial myocardium has not been investigated yet. In this study, we determined the effects of estrogen on key components of atrial renin-angiotensin system: angiotensin-converting enzyme, responsible for generation of angiotensin II and angiotensin-converting enzyme 2, counteracting majority of AngII effects, and different renin-angiotensin system receptors, AT1R, AT2R, and MAS. First, the expression levels of estrogen receptors mRNA were determined in right atrial appendages obtained from patients undergoing heart surgery. The amounts of estrogen receptor and estrogen receptor beta mRNA were similar between women (n = 14) and men (n = 10). Atrial tissue slices (350 mu m) were prepared from male donors which were exposed to estrogen (1-100nM; n = 21) or stimulated at 4Hz for 24h in the presence or absence of 100 nM estrogen (n = 16), respectively. The administration of estrogen did not change mRNA levels of estrogen receptors, but activated MAP kinases, Erk1/2. Furthermore, estrogen increased the amounts of angiotensin-converting enzyme 2-mRNA (1.890.23; P < 0.05) but reduced that of angiotensin-converting enzyme-mRNA (0.78 +/- 0.07, P < 0.05). In addition, the transcript levels of AT2R and MAS were upregulated by estrogen. Pacing of tissue slices significantly increased the angiotensin-converting enzyme/angiotensin-converting enzyme 2 ratio at both the mRNA and protein level. During pacing, administration of estrogen substantially lowered the angiotensin-converting enzyme/angiotensin-converting enzyme 2 ratio at the transcript (0.92 +/- 0.21 vs. 2.12 +/- 0.27 at 4Hz) and protein level (0.94 +/- 0.20 vs. 2.14 +/- 0.3 at 4Hz). Moreover, estrogen elicited anti-inflammatory and anti-oxidative effects on renin-angiotensin system-associated downstream effectors such as pro-oxidative LOX-1 and pro-inflammatory ICAM-1. An antagonist of estrogen receptor reversed these anti-inflammatory and anti-oxidative effects of estrogen significantly. Overall, our results demonstrated that estrogen modifies the local renin-angiotensin system homeostasis and achieves protective effects in atrial myocardium from elderly men.