The role of estrogen receptors in cardiovascular function

雌激素受体在心血管功能中的作用

• 批准号: RGPIN-2018-04732
• 负责人: Pyle, Glen
• 金额: $ 2.11万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=746260
• 关键词: role; estrogen; receptors; cardiovascular; function

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.

雌激素是一种对心脏有复杂影响的激素家族。部分复杂性可归因于3种雌激素受体（ER）（ER-α、ER-β和GPR 30）的存在。在某些情况下，这些受体的激活可以产生相反的功能效应。历史上，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ER激活的快速非基因组效应。我们是第一个发现ER-α激活在<5分钟内改变心脏功能的人。我们项目的目标是确定每个ER如何影响心脏功能并确定细胞内机制。心脏功能在性别之间存在差异。大多数研究报告心脏中ER表达没有差异，但尚不清楚心脏ER的激活是否在每种性别中产生相似的功能效应。研究雌激素对心脏的生理影响往往只使用一种性别，并调查基因组的变化。我们的第一个目标是确定雄性和雌性小鼠如何响应急性ER激活，并确定细胞内机制。我们将评估两种性别急性ER激活后的心脏功能，并研究分子变化。这些研究将提供对ER生理学性别差异的深入了解。许多哺乳动物物种的雌性在年老时经历卵巢雌激素分泌的自然下降。在人类中，这会导致更年期。绝经发生在绝经前后低雌激素产生阶段的过渡之后。在生命后期雌激素的损失被认为是导致心脏衰老的原因，但在进入更年期的过渡期间心脏如何变化以及更年期后心脏如何继续变化尚不清楚。我们的第二个目标是确定心脏在绝经期和绝经后时期是如何改变的，以及对急性ER激活的反应是如何受到影响的。植物雌激素是植物基化合物，在饮食中越来越普遍。高达25%的人类婴儿被喂食富含植物雌激素的大豆配方奶粉，许多宠物食品都补充了大豆产品。世界上大多数大豆作物都被加工并用作食用动物的饲料。尽管植物雌激素在几种动物中的消费广泛且不断增加，但对这些化合物对心脏生理学的影响或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，提示不同的作用机制。我们发现，膳食植物雌激素逆转雌激素损失的影响，在小鼠，但没有人已经检查了心脏的生理影响，在完整的女性或男性。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。