Non-nuclear estrogen receptor alpha activation in endothelium reduces cardiac ischemia-reperfusion injury in mice.
Non-nuclear estrogen receptor alpha activation in endothelium reduces cardiac ischemia-reperfusion injury in mice.
复制标题
DOI：
10.1016/j.yjmcc.2017.04.004
复制
发表时间：
2017-06
影响因子：
5
通讯作者：
Murphy E
中科院分区：
文献类型：
--
作者：
Menazza S;Sun J;Appachi S;Chambliss KL;Kim SH;Aponte A;Khan S;Katzenellenbogen JA;Katzenellenbogen BS;Shaul PW;Murphy E
包括雌激素受体 (ER) 在内的类固醇激素受体通常充当配体调节的转录因子。然而，雌激素还通过与与激酶偶联的核外 ER（ERα、ERβ 和 G 蛋白偶联 ER 或 GPER）结合而引发细胞效应。核外 ER 作用如何影响心脏缺血再灌注 (I/R) 损伤尚不清楚。我们用雌二醇 (E2) 或雌激素-树枝状大分子缀合物 (EDC) 治疗卵巢切除的野生型雌性小鼠，选择性激活核外 ER，或载体干预两周。然后在孤立的 Langendorff 灌注心脏中评估 I/R 损伤。 E2 治疗两周可显着减少梗塞面积并改善缺血后收缩功能。同样，与载体治疗的心脏相比，EDC 治疗显着减少了梗塞面积并增加了缺血后功能恢复。 EDC 还引起心肌蛋白 S-亚硝基化的增加，这与之前显示这种翻译后修饰在心脏保护中的作用的研究一致。为了进一步支持 S-亚硝基化作用，抑制一氧化氮合酶（但不抑制可溶性鸟苷酸环化酶）会阻断 EDC 介导的保护。 ICI182,780是G蛋白偶联雌激素受体（GPER）的激动剂以及ERα和ERβ的拮抗剂，但施用ICI182,780并没有产生保护作用；然而，ICI182,780 显着阻断 EDC 介导的心脏保护作用，表明 ERα 和/或 ERβ 参与其中。在确定特定 ER 亚型和相关细胞靶标的研究中，EDC 减少了心肌细胞中缺乏 ERα 的小鼠的梗塞面积并改善了功能恢复。相反，内皮细胞 ERα 缺陷的小鼠则失去了保护作用。因此，内皮细胞核外 ERα 激活可减少小鼠心脏 I/R 损伤，这可能导致蛋白质 S-亚硝基化增加。由于 EDC 不会刺激子宫生长，因此在临床环境中，EDC 类化合物可以提供心肌保护，而不会产生不良的子宫营养和促癌作用。
Steroid hormone receptors including estrogen receptors (ER) classically function as ligand-regulated transcription factors. However, estrogens also elicit cellular effects through binding to extra-nuclear ER (ERα, ERβ, and G protein-coupled ER or GPER) that are coupled to kinases. How extra-nuclear ER actions impact cardiac ischemia-reperfusion (I/R) injury is unknown. We treated ovariectomized wild-type female mice with estradiol (E2) or an estrogen-dendrimer conjugate (EDC), which selectively activates extra-nuclear ER, or vehicle interventions for two weeks. I/R injury was then evaluated in isolated Langendorff perfused hearts. Two weeks of treatment with E2 significantly decreased infarct size and improved post-ischemic contractile function. Similarly, EDC treatment significantly decreased infarct size and increased post-ischemic functional recovery compared to vehicle-treated hearts. EDC also caused an increase in myocardial protein S-nitrosylation, consistent with previous studies showing a role for this post-translational modification in cardioprotection. In further support of a role for S-nitrosylation, inhibition of nitric oxide synthase, but not soluble guanylyl cyclase blocks the EDC mediated protection. The administration of ICI182,780, which is an agonist of G-protein coupled estrogen receptor (GPER) and an antagonist of ERα and ERβ, did not result in protection; however, ICI182,780 significantly blocked EDC-mediated cardioprotection, indicating participation of ERα and/or ERβ. In studies determining the specific ER subtype and cellular target involved, EDC decreased infarct size and improved functional recovery in mice lacking ERα in cardiomyocytes. In contrast, protection was lost in mice deficient in endothelial cell ERα. Thus, extra-nuclear ERα activation in endothelium reduces cardiac I/R injury in mice, and this likely entails increased protein S-nitrosylation. Since EDC does not stimulate uterine growth, in the clinical setting EDC-like compounds may provide myocardial protection without undesired uterotrophic and cancer-promoting effects.
登录
查看更多内容
影响因子：
5
作者：
Gabel, Scott A;Walker, Vickie R;Murphy, Elizabeth
通讯作者：
Murphy, Elizabeth
影响因子：
37.8
作者：
Lin J;Steenbergen C;Murphy E;Sun J
通讯作者：
Sun J
影响因子：
15.9
作者：
Chambliss, Ken L.;Wu, Qian;Shaul, Philip W.
通讯作者：
Shaul, Philip W.
影响因子：
2.5
作者：
Alva, JA;Zovein, AC;Iruela-Arispe, ML
通讯作者：
Iruela-Arispe, ML
影响因子：
--
作者：
Filardo, EJ;Quinn, JA;Bland, KI
通讯作者：
Bland, KI