Activation of G protein-coupled estrogen receptor protects intestine from ischemia/reperfusion injury in mice by protecting the crypt cell proliferation
Activation of G protein-coupled estrogen receptor protects intestine from ischemia/reperfusion injury in mice by protecting the crypt cell proliferation
复制标题
G蛋白偶联雌激素受体的激活通过保护隐窝细胞增殖来保护小鼠肠道免受缺血/再灌注损伤
DOI：
10.1042/cs20180919
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发表时间：
2019-02-14
期刊：
影响因子：
6
通讯作者：
Xue, Bing
中科院分区：
文献类型：
--
作者：
Chai, Shiquan;Liu, Kaixuan;Xue, Bing
肠缺血/再灌注（I/R）损伤是临床上常见的并发症，与手术或创伤后患者的高死亡率有关。雌激素对肠I/R损伤有一定的保护作用，但其受体类型尚不完全清楚。本研究旨在探讨G蛋白偶联雌激素受体（GPER）对肠缺血再灌注损伤的保护作用及其机制。通过夹闭（45 min）上级肠系膜动脉，随后进行4 h肠再灌注，使成年雄性C57 BL/6小鼠经受肠I/R损伤。我们的结果表明，选择性GPER阻断剂取消了雌激素对肠I/R损伤的保护作用。选择性GPER激动剂G-1可显著减轻I/R所致的肠黏膜损伤、中性粒细胞浸润、TNF-α和环氧合酶-2（考克斯-2）表达上调，恢复受损的肠屏障功能。G-1可改善I/R所致的腺窝细胞增殖能力的下降，使绒毛高度和腺窝深度的下降得到恢复。诱导型一氧化氮合酶（iNOS）表达的上调I/R治疗后减弱G-1管理。在肠I/R模型中，选择性iNOS抑制剂对肠腺细胞增殖的促进作用与G-1相似。在隐窝中富含亮氨酸重复序列的G蛋白偶联受体5（Lgr 5）阳性干细胞中表达GPER和iNOS。总之，这些发现表明，GPER激活可以促进肠损伤后的上皮细胞修复，这至少部分是通过抑制肠干细胞（ISCs）中的iNOS表达而发生的。GPER可能是肠I/R损伤的一个新的治疗靶点。
The intestinal ischemia/reperfusion (I/R) injury is a common clinical event related with high mortality in patients undergoing surgery or trauma. Estrogen exerts salutary effect on intestinal I/R injury, but the receptor type is not totally understood. We aimed to identify whether the G protein-coupled estrogen receptor (GPER) could protect the intestine against I/R injury and explored the mechanism. Adult male C57BL/6 mice were subjected to intestinal I/R injury by clamping (45 min) of the superior mesenteric artery followed by 4 h of intestinal reperfusion. Our results revealed that the selective GPER blocker abolished the protective effect of estrogen on intestinal I/R injury. Selective GPER agonist G-1 significantly alleviated I/R-induced intestinal mucosal damage, neutrophil infiltration, up-regulation of TNF-a and cyclooxygenase-2 (Cox-2) expression, and restored impaired intestinal barrier function. G-1 could ameliorate the impaired crypt cell proliferation ability induced by I/R and restore the decrease in villus height and crypt depth. The up-regulation of inducible nitric oxide synthase (iNOS) expression after I/R treatment was attenuated by G-1 administration. Moreover, selective iNOS inhibitor had a similar effect with G-1 on promoting the proliferation of crypt cells in the intestinal I/R model. Both GPER and iNOS were expressed in leucine-rich repeat containing G-protein coupled receptor 5 (Lgr5) positive stem cells in crypt. Together, these findings demonstrate that GPER activation can prompt epithelial cell repair following intestinal injury, which occurred at least in part by inhibiting the iNOS expression in intestinal stem cells (ISCs). GPER may be a novel therapeutic target for intestinal I/R injury.