The effects of (-)-epicatechin on endothelial cells involve the G protein-coupled estrogen receptor (GPER).
The effects of (-)-epicatechin on endothelial cells involve the G protein-coupled estrogen receptor (GPER).
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DOI：
10.1016/j.phrs.2015.08.014
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发表时间：
2015-10
影响因子：
9.3
通讯作者：
Villarreal F
中科院分区：
文献类型：
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作者：
Moreno-Ulloa A;Mendez-Luna D;Beltran-Partida E;Castillo C;Guevara G;Ramirez-Sanchez I;Correa-Basurto J;Ceballos G;Villarreal F
我们提供的证据表明，(−)-表儿茶素((−)-EPI)对内皮细胞一氧化氮(NO)产生的刺激作用可能与细胞表面受体的参与有关。到目前为止，这种实体还没有得到充分的阐明。G蛋白偶联雌激素受体是一种细胞表面受体，与已报道的(−)-雌激素受体类似，它与心血管系统的保护作用和细胞内信号通路的激活(包括NO产生)有关。在牛冠状动脉内皮细胞(BCAEC)中，通过共聚焦成像，我们证明在细胞表面和F-肌动蛋白细丝上存在GPER。在电子计算机研究中，我们证明了(−)-EPI与GPER之间良好的结合方式。这种结合与GPER激动剂G1的结合相当。通过使用选择性阻断剂，我们证明了(−)-EPI对ERK1/2和CaMKII的激活依赖于GPER/c-SRC/EGFR轴，类似于G1所注意到的那些效应。我们还通过使用siRNA证明了GPER在(−)-EPI介导ERK1/2激活中所起的作用。GPER似乎与非GαI/O或GαS蛋白亚型偶联。为了将我们的发现外推到体外模型，我们采用了苯肾上腺素预收缩的主动脉环，证明(−)-EPI可以通过激活GPER介导血管扩张。总之，我们提供的证据表明，GPER是(−)-EPI效应的潜在中介，并强调了GPER在心血管系统保护中的重要作用。
We have provided evidence that the stimulatory effects of (−)-epicatechin ((−)-EPI) on endothelial cell nitric oxide (NO) production may involve the participation of a cell-surface receptor. Thus far, such entity(ies) has not been fully elucidated. The G protein-coupled estrogen receptor (GPER) is a cell-surface receptor that has been linked to protective effects on the cardiovascular system and activation of intracellular signaling pathways (including NO production) similar to those reported with (−)-EPI. In bovine coronary artery endothelial cells (BCAEC) by the use of confocal imaging, we evidence the presence of GPER at the cell-surface and on F-actin filaments. Using in silico studies we document the favorable binding mode between (−)-EPI and GPER. Such binding is comparable to that of the GPER agonist, G1. By the use of selective blockers, we demonstrate that the activation of ERK 1/2 and CaMKII by (−)-EPI is dependent on the GPER/c-SRC/EGFR axis mimicking those effects noted with G1. We also evidence by the use of siRNA the role that GPER has on mediating ERK1/2 activation by (−)-EPI. GPER appears to be coupled to a non Gαi/o or Gαs, protein subtype. To extrapolate our findings to an ex vivo model, we employed phenylephrine pre-contracted aortic rings evidencing that (−)-EPI can mediate vasodilation through GPER activation. In conclusion, we provide evidence that suggests the GPER as a potential mediator of (−)-EPI effects and highlights the important role that GPER may have on cardiovascular system protection.