Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Cosenza, Italy.
PLoS One. 2013 Aug 9;8(8):e69322. doi: 10.1371/journal.pone.0069322. eCollection 2013.
Estrogens promote beneficial effects in the cardiovascular system mainly through the estrogen receptor (ER)α and ERβ, which act as ligand-gated transcription factors. Recently, the G protein-coupled estrogen receptor (GPER) has been implicated in the estrogenic signaling in diverse tissues, including the cardiovascular system. In this study, we demonstrate that left ventricles of male Spontaneously Hypertensive Rats (SHR) express higher levels of GPER compared to normotensive Wistar Kyoto (WKY) rats. In addition, we show that the selective GPER agonist G-1 induces negative inotropic and lusitropic effects to a higher extent in isolated and Langendorff perfused hearts of male SHR compared to WKY rats. These cardiotropic effects elicited by G-1 involved the GPER/eNOS transduction signaling, as determined by using the GPER antagonist G15 and the eNOS inhibitor L-NIO. Similarly, the G-1 induced activation of ERK1/2, AKT, GSK3β, c-Jun and eNOS was abrogated by G15, while L-NIO prevented only the eNOS phosphorylation. In hypoxic Langendorff perfused WKY rat heart preparations, we also found an increased expression of GPER along with that of the hypoxic mediator HIF-1α and the fibrotic marker CTGF. Interestingly, G15 and L-NIO prevented the ability of G-1 to down-regulate the expression of both HIF-1α and CTGF, which were found expressed to a higher extent in SHR compared to WKY rat hearts. Collectively, the present study provides novel data into the potential role played by GPER in hypertensive disease on the basis of its involvement in myocardial inotropism and lusitropism as well as the expression of the apoptotic HIF-1α and fibrotic CTGF factors. Hence, GPER may be considered as a useful target in the treatment of some cardiac dysfunctions associated with stressful conditions like the essential hypertension.
雌激素主要通过雌激素受体 (ER)α 和 ERβ 发挥有益的心血管作用，后者作为配体门控转录因子发挥作用。最近，G 蛋白偶联雌激素受体 (GPER) 已被牵涉到包括心血管系统在内的多种组织中的雌激素信号传导中。在这项研究中，我们证明雄性自发性高血压大鼠 (SHR) 的左心室表达的 GPER 水平高于正常血压的 Wistar Kyoto (WKY) 大鼠。此外，我们还表明，选择性 GPER 激动剂 G-1 在分离的和 Langendorff 灌注的雄性 SHR 心脏中引起的负性肌力和正性松弛作用比 WKY 大鼠更为显著。通过使用 GPER 拮抗剂 G15 和 eNOS 抑制剂 L-NIO，确定这些由 G-1 引起的心脏作用涉及 GPER/eNOS 转导信号。同样，G-1 诱导的 ERK1/2、AKT、GSK3β、c-Jun 和 eNOS 的激活被 G15 阻断，而 L-NIO 仅阻止 eNOS 的磷酸化。在缺氧的 Langendorff 灌注的 WKY 大鼠心脏制剂中，我们还发现 GPER 的表达增加，同时缺氧介质 HIF-1α 和纤维化标记物 CTGF 的表达也增加。有趣的是，G15 和 L-NIO 阻止了 G-1 下调 HIF-1α 和 CTGF 表达的能力，而在 SHR 心脏中发现这两种因子的表达水平高于 WKY 大鼠心脏。总之，本研究提供了新的数据，表明 GPER 在高血压疾病中的潜在作用是基于其对心肌变力性和变松弛性的影响，以及凋亡 HIF-1α 和纤维化 CTGF 因子的表达。因此，GPER 可被视为治疗与应激状态相关的某些心脏功能障碍的有用靶点，如原发性高血压。
