Department of Anesthesiology, Wake Forest School of Medicine, Winston Salem, North Carolina; Department of Internal Medicine-Molecular Medicine, Wake Forest School of Medicine, Winston Salem, North Carolina.
Department of Anesthesiology, Wake Forest School of Medicine, Winston Salem, North Carolina.
Transl Res. 2018 Sep;199:39-51. doi: 10.1016/j.trsl.2018.04.005. Epub 2018 Apr 25.
Oxidative stress has been implicated in the unfavorable changes in cardiac function and remodeling that occur after ovarian estrogen loss. Using ovariectomized rat models, we previously reported that the cardioprotective actions of estrogen are mediated by the G protein-coupled estrogen receptor (GPER). Here, in 9-month-old, female cardiomyocyte-specific GPER knockout (KO) mice vs sex- and age-matched wild-type (WT) mice, we found increased cardiac oxidative stress and oxidant damage, measured as a decreased ratio of reduced glutathione to oxidized glutathione, increased 4-hydroxynonenal and 8-hydroxy-2'-deoxyguanosine (8-oxo-DG) staining, and increased expression of oxidative stress-related genes. GPER KO mice also displayed increased heart weight, cardiac collagen deposition, and Doppler-derived filling pressure, and decreased percent fractional shortening and early mitral annular velocity compared with WT controls. Treatment of GPER KO mice for 8 weeks with phosphonium [10-(4,5-dimethoxy-2-methyl 3,6-dioxo-1,4-cyclohexadien-1-yl)decyl] triphenyl-,mesylate (MitoQ), a mitochondria-targeted antioxidant, significantly attenuated these measures of cardiac dysfunction, and MitoQ decreased 8-oxo-DG intensity compared with treatment with an inactive comparator compound, (1-decyl)triphenylphosphonium bromide (P <0.05). A real-time polymerase chain reaction array analysis of 84 oxidative stress and antioxidant defense genes revealed that MitoQ attenuates the increase in NADPH oxidase 4 and prostaglandin-endoperoxide synthase 2 and the decrease in uncoupling protein 3 and glutathione S-transferase kappa 1 seen in GPER KO mice. Our findings suggest that the cardioprotective effects of GPER include an antioxidant role and that targeted strategies to limit oxidative stress after early noncancerous surgical extirpation of ovaries or menopause may help limit alterations in cardiac structure and function related to estrogen loss.
氧化应激与卵巢雌激素丧失后心脏功能和重构的不利变化有关。我们之前使用卵巢切除大鼠模型报告称，雌激素的心脏保护作用是由 G 蛋白偶联雌激素受体（GPER）介导的。在这里，在 9 月龄的雌性心肌细胞特异性 GPER 敲除（KO）小鼠与性别和年龄匹配的野生型（WT）小鼠中，我们发现心脏氧化应激和氧化剂损伤增加，表现为还原型谷胱甘肽与氧化型谷胱甘肽的比例降低，4-羟基壬烯醛和 8-羟基-2'-脱氧鸟苷（8-oxo-DG）染色增加，以及与氧化应激相关的基因表达增加。与 WT 对照组相比，GPER KO 小鼠还表现出心脏重量增加、心脏胶原沉积和多普勒衍生的充盈压增加，以及百分比缩短分数和早期二尖瓣环速度降低。用磷 [10-（4,5-二甲氧基-2-甲基 3,6-二氧代-1,4-环己二烯-1-基）癸基]三苯基-，甲磺酸酯（MitoQ）治疗 8 周后，GPER KO 小鼠的心脏功能障碍得到了显著改善，并且与活性对照化合物（1-癸基）三苯基溴化膦（P <0.05）相比，MitoQ 降低了 8-oxo-DG 强度。对 84 种氧化应激和抗氧化防御基因的实时聚合酶链反应分析显示，MitoQ 可减轻 GPER KO 小鼠中 NADPH 氧化酶 4 和前列腺素内过氧化物合酶 2 的增加以及解偶联蛋白 3 和谷胱甘肽 S-转移酶 kappa 1 的减少。我们的研究结果表明，GPER 的心脏保护作用包括抗氧化作用，并且在早期非癌性卵巢切除或绝经后限制卵巢雌激素丧失相关心脏结构和功能改变的靶向抗氧化应激策略可能有助于限制。
