Estrogen increases iNOS expression in the ovine coronary artery.
Estrogen increases iNOS expression in the ovine coronary artery.
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雌激素增加绵羊冠状动脉中 iNOS 的表达。
DOI：
10.1152/ajpheart.00397.2000
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发表时间：
2002
期刊：
影响因子：
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通讯作者：
Clark,KennethE
中科院分区：
文献类型：
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作者：
Mershon,JohnL;Baker,RScott;Clark,KennethE
雌激素被认为可以保护绝经后女性免受冠状动脉血管疾病的侵袭，部分原因是增加了一氧化氮(NO)的产生。在这项研究中，我们研究了诱导型一氧化氮合酶(INOS)的转录激活可能是雌激素诱导的冠状动脉血流量增加的一个组成部分。用多普勒血流探头对22只母羊的左回旋支、冠状动脉和肺动脉进行检测。9只绵羊静脉注射17β-雌二醇(1μg/kg)，观察16 h后冠脉血流量增加22±4%，2 h达高峰(P<；0.01)。为探讨雌激素对绵羊冠状动脉一氧化氮合酶表达的影响，17只非仪器化动物在注射雌二醇或赋形剂后2 h处死。半定量RT-PCR法检测冠脉组织中诱导型一氧化氮合酶和内皮型一氧化氮合酶的表达。根据本研究分离到的绵羊内皮型一氧化氮合酶和诱导型一氧化氮合酶的部分基因克隆，设计了相应的聚合酶链式反应引物。雌二醇组iNOS表达显著增加(27倍)，而eNOS表达明显减弱(2倍)。为了在体内证实这些效应，另外的仪器化动物接受雌激素受体拮抗剂ICI-182,780(n=5)，诱导型一氧化氮合酶拮抗剂地塞米松(n=5)或核因子-κB的抑制剂吡咯烷二硫代氨基甲酸(n=5)。这三种拮抗剂均可抑制雌激素引起的冠脉血流量增加和心输出量增加85%以上。这些结果有力地支持了这样的假设，即17β-雌二醇通过ER依赖的机制增加了未麻醉未怀孕母羊的冠脉血流量，从而导致eNOS和iNOS表达的增加。
Estrogen is believed to protect postmenopausal women from coronary vascular disease, in part by increasing production of nitric oxide (NO). In this study, we investigated the possibility that transcriptional activation of inducible NO synthase (iNOS) is responsible for a component of the estrogen-induced increase in coronary blood flow. Twenty-two ewes were instrumented with Doppler flow probes on their left circumflex coronary and pulmonary arteries. Nine ewes received 17β-estradiol (1 μg/kg), and the coronary vascular response was followed for 16 h. Estradiol significantly increased coronary blood flow by 22 ± 4% over baseline and the peak response occurred at 2 h (P< 0.01). To examine the effect of estrogen on NOS expression in the ovine coronary artery, 17 noninstrumented animals were killed 2 h after administration of estradiol or vehicle. Coronary arteries were analyzed for ovine iNOS and endothelial NOS (eNOS) expression by semiquantitative RT-PCR. PCR primers were based on partial cDNA clones for ovine eNOS and iNOS isolated as part of this study. The expression of iNOS was significantly increased (27-fold) by the administration of estradiol, whereas the expression of eNOS was much weaker (2-fold). To confirm these effects in vivo, additional instrumented animals received either the estrogen receptor (ER) antagonist ICI-182,780 (n= 5), the iNOS antagonist dexamethasone (n= 5), or pyrrolidine dithiocarbamic acid, an inhibitor of nuclear factor-κB (n= 5). All three antagonists inhibited estrogen-induced increases in coronary blood flow and increases in cardiac output by over 85%. These results strongly support the hypothesis that 17β-estradiol increases coronary blood flow in the unanesthetized nonpregnant ewe via an ER-dependent mechanism that results in an increase in both eNOS and iNOS expression.