LXRβ/estrogen receptor-α signaling in lipid rafts preserves endothelial integrity
LXRβ/estrogen receptor-α signaling in lipid rafts preserves endothelial integrity
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DOI：
10.1172/jci66533
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发表时间：
2013-08-01
影响因子：
15.9
通讯作者：
Umetani, Michihisa
中科院分区：
文献类型：
--
作者：
Ishikawa, Tomonori;Yuhanna, Ivan S.;Umetani, Michihisa
肝脏X受体（LXR）由胆固醇衍生的氧固醇刺激，并作为转录因子调节基因表达以响应胆固醇的变化。在本研究中，我们研究了LXR在血管内皮细胞（EC）中的作用，发现LXR β具有非核功能，并通过激活内皮NOS（eNOS）刺激EC迁移。这一过程由雌激素受体α（ER α）介导。LXR激活促进LXR β与ER α配体结合域的直接结合，并启动了一个需要ER α Ser 118通过PI 3 K/AKT磷酸化的细胞核信号级联反应。进一步的研究表明，LXR β和ER α是共定位和功能耦合在EC质膜小窝/脂质。木筏在离体主动脉环中，LXR激活NOS引起舒张，而在小鼠中，LXR激活通过LXR β和ER α依赖性过程刺激颈动脉再内皮化。这些研究表明，LXR β在EC小窝/脂筏中具有非核功能，需要与ER α发生串扰，从而促进NO产生并维持体内内皮单层完整性。
Liver X receptors (LXR) are stimulated by cholesterol-derived oxysterols and serve as transcription factors to regulate gene expression in response to alterations in cholesterol. In the present study, we investigated the role of LXRs in vascular endothelial cells (ECs) and discovered that LXR beta has nonnuclear function and stimulates EC migration by activating endothelial NOS (eNOS). This process is mediated by estrogen receptor-alpha (ER alpha). LXR activation promoted the direct binding of LXR beta to the ligand-binding domain of ER alpha and initiated an extranuclear signaling cascade that requires ER alpha Ser118 phosphorylation by PI3K/AKT. Further studies revealed that LXR beta and ER alpha are colocalized and functionally coupled in EC plasma membrane caveolae/lipid. rafts. In isolated aortic rings, LXR activation of NOS caused relaxation, while in mice, LXR activation stimulated carotid artery reendothelialization via LXR beta- and ER alpha-dependent processes. These studies demonstrate that LXR beta has nonnuclear function in EC caveolae/lipid rafts that entails crosstalk with ER alpha, which promotes NO production and maintains endothelial monolayer integrity in vivo.