The role of estrogen receptors in cardiovascular function

雌激素是一类对心脏有复杂影响的激素。部分复杂性可归因于3种雌激素受体（ER） （ER- α， ER- β和GPR30）的存在。在某些情况下，这些受体的激活会产生相反的功能效应。从历史上看，雌激素对心脏的影响归因于基因表达的变化，但最近报道了内质网激活的快速非基因组效应。我们首次证明er - α激活在<5分钟内改变心脏功能。我们项目的目标是确定每种内质网如何影响心脏功能，并确定细胞内机制。心脏功能因性别而异。大多数研究报告在心脏中内质网的表达没有差异，但尚不清楚心脏内质网的激活是否在两性中产生类似的功能作用。检查雌激素对心脏生理影响的研究往往只使用一个性别，并调查基因组变化。我们的第一个目标是确定雄性和雌性小鼠对急性内质网激活的反应，并确定细胞内机制。我们将评估两性急性内质网激活后的心功能，并研究分子变化。这些研究将有助于深入了解内质网生理学的性别差异。许多哺乳动物的雌性在年龄较大时卵巢产生的雌激素会自然下降。在人类中，这会导致更年期。绝经发生在低雌激素产生期的过渡之后。人们认为，晚年雌激素的减少会导致心脏老化，但心脏在进入更年期期间如何变化，以及在更年期后如何继续变化，目前尚不清楚。我们的第二个目标是确定心脏在围绝经期和绝经后是如何改变的，以及急性内质网激活的反应是如何受到影响的。植物雌激素是基于植物的化合物，在饮食中越来越普遍。多达25%的人类婴儿食用富含植物雌激素的大豆配方奶粉，许多宠物食品也添加了豆制品。世界上大部分大豆作物都经过加工，用作食用动物的饲料。尽管植物雌激素在一些动物物种中广泛且不断增加，但人们对这些化合物对心脏生理的影响及其作用机制知之甚少。植物雌激素的作用可能与动物雌激素相反，表明其作用机制不同。我们发现，饮食中的植物雌激素可以逆转小鼠雌激素损失的影响，但没有人研究过对完整女性或男性心脏的生理影响。我们的第三个目标是通过超声心动图和心导管检查研究膳食植物雌激素对整个心脏功能的影响，并确定细胞内机制。

Estrogens are a family of hormones that have complex effects on the heart. Part of the complexity can be attributed to the presence of 3 estrogen receptors (ER) (ER-alpha, ER-beta, and GPR30). In some cases the activation of these receptors can produce opposing functional effects. Historically the impact of estrogens on the heart have been attributed to changes in gene expression, but more recently rapid, non-genomic effects of ER activation have been reported. We were the first to show that ER-alpha activation changes heart function in <5 min. The objectives of our program are to determine how each ER affects heart function and to identify the intracellular mechanisms.Heart function differs between sexes. Most studies report no differences in ER expression in the heart, but it is unknown if the activation of cardiac ER produces similar functional effects in each sex. Studies examining the physiological effects of estrogens on the heart tend to use only one sex and investigate genomic changes. Our first objective is to determine how male and female mice respond to acute ER activation, and identify the intracellular mechanisms. We will assess heart function following acute ER activation in both sexes, and investigate the molecular changes. These studies will provide insight into sex differences in ER physiology.Females of many mammalian species experience a natural decline in estrogen production by the ovaries at older ages. In humans this results in menopause. Menopause occurs after a transition through the low estrogen producing phase peri-menopause'. The loss of estrogens later in life are proposed to contribute to the ageing of the heart, but how the heart changes during the transition into menopause and how it continues to change following menopause is not clear. Our second objective is to determine how the heart is altered during the peri- and post-menopausal periods, and how the response to acute ER activation is affected.Phytoestrogens are plant-based compounds that are increasingly prevalent in diets. Up to 25% of human infants are fed soy based formula that is rich in phytoestrogens, and many pet foods are supplemented with soy products. The majority of the world's soybean crops are processed and used as feed for food animals. Despite widespread and increasing consumption of phytoestrogens by several animal species, little is known about the effects of these compounds on cardiac physiology, or their mechanisms of action. The effects of phytoestrogens can be opposite to that of animal estrogens, suggesting distinct mechanisms of action. We showed that dietary phytoestrogens reverse the effects of estrogen loss in mice, but no one has examined the physiological effects on the heart in intact female or males. Our third objective is to investigate the impact of dietary phytoestrogens on whole heart function by echocardiography and cardiac catheterization, and to identify intracellular mechanisms.