Estrogen inhibits vascular calcification in rats via hypoxia-induced factor-1a signaling
Estrogen inhibits vascular calcification in rats via hypoxia-induced factor-1a signaling
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雌激素通过缺氧诱导的因子 1a 信号传导抑制大鼠血管钙化
DOI：
10.1177/1708538120904297
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发表时间：
2020
期刊：
影响因子：
1.1
通讯作者：
Hong Liu
中科院分区：
文献类型：
--
作者：
Xinhua Wu;Qiuyan Zhao;Zhangrong Chen;Yong-Jian Geng;Wangting Zhang;Qingqing Zhou;Wei Yang;quanyi Liu;Hong Liu
目的：钙化可作为动脉粥样硬化相关血管疾病的替代指标，而冠状动脉钙化是由多种致病因素介导的。雌激素是保护动脉壁免受动脉粥样硬化的已知因素，但其在冠状动脉钙化发展中的作用仍不清楚。本研究验证了雌激素通过缺氧诱导的因子1a途径抑制冠状动脉钙化的假设。方法：对8周龄健康雌性Sprague-Dawley大鼠进行去势，并口服维生素D3来建立。给予缺氧诱导因子1抑制剂，检测其对血管钙化以及骨形态发生蛋白2和runt相关转录因子2表达的影响。在存在或不存在E2(17b-雌二醇)和骨形态发生蛋白2 siRNA干预的情况下，用CaCl2诱导大鼠主动脉平滑肌细胞的血管平滑肌细胞钙化。结果：ELISA测定，去卵巢大鼠的雌激素水平显着降低。与未钙化的血管细胞相比，有钙化的血管细胞缺氧诱导因子1a mRNA和蛋白的表达显着增加(p<0.01)。 E2处理降低了体外血管细胞钙化和细胞钙结节中的钙浓度(p<0.05)。 E2还降低了缺氧诱导的因子1a mRNA和蛋白的水平(p<0.01)。口服缺氧诱导因子 1a 抑制剂二甲基氧杂环丁烷可减轻去势大鼠的血管钙化以及成骨相关转录因子、骨形态发生蛋白 2 和 RUNX2 的表达（p<0.01）。最后，骨形态发生蛋白 2 siRNA 治疗降低了 A7r5 钙化细胞中 p-Smad1/5/8 的水平 (p<0.01)。结论：雌激素缺乏会增强血管钙化。雌激素治疗可减少大鼠缺氧诱导因子1a的表达以及血管钙化。雌激素作用的发生方式依赖于缺氧诱导的因子 1a 对骨形态发生蛋白 2 和下游 Smad1/5/8 的调节。
Objective: Calcification serves as a surrogate for atherosclerosis-associated vascular diseases, and coronary artery.calcification is mediated by multiple pathogenic factors. Estrogen is a known factor that protects the arterial wall against.atherosclerosis, but its role in the coronary artery calcification development remains largely unclear. This study tested.the hypothesis that estrogen inhibits coronary artery calcification via the hypoxia-induced factor-1a pathway..Methods: Eight-week-old healthy female Sprague–Dawley rats were castrated, and vitamin D3 was administered orally.to establish. Hypoxia-induced factor-1 inhibitor was administered to test its effect on vascular calcification and expression.of bone morphogenetic protein 2 and runt-related transcription factor-2. Vascular smooth muscle cell calcification.was induced with CaCl2 in rat aortic smooth muscle cells in the presence or absence of E2(17b-estradiol) and bone.morphogenetic protein 2 siRNA intervention..Results: The estrogen levels in ovariectomized rats were significantly decreased, as determined by ELISA. Expression of.hypoxia-induced factor-1a mRNA and protein was significantly increased in vascular cells with calcification as compared.to those without calcification (p<0.01). E2 treatment decreased the calcium concentration in vascular cell calcification.and cell calcium nodules in vitro (p<0.05). E2 also lowered the levels of hypoxia-induced factor-1a mRNA and protein.(p<0.01). Oral administration of the hypoxia-induced factor-1a inhibitor dimethyloxetane in castrated rats alleviated.vascular calcification and expression of osteogenesis-related transcription factors, bone morphogenetic protein 2 and.RUNX2 (p<0.01). Finally, bone morphogenetic protein 2 siRNA treatment decreased the levels of p-Smad1/5/8 in A7r5.calcification cells (p<0.01)..Conclusion: Estrogen deficiency enhances vascular calcification. Treatment with estrogen reduces the expression of.hypoxia-induced factor-1a as well as vascular calcification in rats. The estrogen effects occur in a fashion dependent on.hypoxia-induced factor-1a regulation of bone morphogenetic protein-2 and downstream Smad1/5/8.