A novel role for endothelial mineralocorticoid receptors in obesity-associated cardiovascular disease in females

内皮盐皮质激素受体在女性肥胖相关心血管疾病中的新作用

• 批准号: 10654762
• 负责人: Jessica L. Faulkner
• 金额: $ 24.9万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10654762
• 关键词: Adipose tissue; Adrenal Glands; Aldosterone; Animal Model; Blood Vessels; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cell Culture Techniques; Cells; Clinical; Clinical Data; Collaborations; Data; Data Reporting; Endothelial Cells; Endothelium; Environment; Event; Excision; Exhibits; Faculty; Female; Functional disorder; Genetic; Genetic Transcription; Goals; High Risk Woman; Hormones; Human; Hypertension; Hypoxia; Impairment; In Vitro; Ischemia; Knowledge; Leptin; Marketing; Mediating; Mediator; Mentors; Mineralocorticoid Receptor; Molecular; Mus; Myocardial Infarction; Obesity; Obesity Epidemic; Obesity associated cardiovascular disease; Outcome; Ovariectomy; Pathway interactions; Perfusion; Pharmacologic Substance; Phase; Plasma; Positioning Attribute; Pre-Eclampsia; Pregnancy; Premenopause; Prevention strategy; Production; Progesterone; Progesterone Receptors; Protein Kinase C; Proteins; Publishing; Rattus; Receptor Activation; Receptor Inhibition; Regulation; Reporting; Research Personnel; Resources; Role; Scheme; Sex Differences; Stroke; Techniques; Testing; Therapeutic; Training; Transcript; Transgenic Animals; Transgenic Mice; Treatment outcome; Universities; Uterus; Vascular Diseases; Vascular Endothelium; Woman; Work; antagonist; blood pressure elevation; cardiovascular risk factor; efficacious treatment; endothelial dysfunction; epithelial Na+ channel; female sex hormone; field study; human tissue; hypertensive; improved; male; men; mouse model; novel; obesity prevention; pharmacologic; pregnant; pressure; prevent; protective effect; protein expression; receptor expression; response; sex; tenure track; therapeutic target; translational approach; treatment strategy; young woman

PROJECT SUMMARY Obese premenopausal women are at higher risk for vascular disorders than obese men demonstrating that obesity negates protective effects of female sex hormones, however, the underlying mechanisms are unknown. The adipose-derived hormone leptin mediates hypertension in obese males and females, however, the mechanistic pathways are sex-specific. Clinical data report better cardiovascular treatment outcomes in females treated with mineralocorticoid receptor (MR) antagonists than males. In accordance, our lab published that leptin- induced hypertension and endothelial dysfunction is mediated by the aldosterone-MR axis in females. In this proposal we provide a number of novel preliminary data: 1. female mice are more sensitive to aldosterone- induced endothelial dysfunction 2. endothelial-specific MR (ECMR) deletion and epithelial sodium channel (ENaC) antagonism prevents leptin-induced endothelial impairment in females 3. endothelial cells of female mice and humans express more ECMR than males 4. ovariectomy blunts ECMR expression, which is restored by progesterone 5. ECMR expression correlates with progesterone levels in cycling and pregnant mice 6. protein kinase C (PKC) inhibition prevents progesterone-stimulated ECMR expression 7. pregnant mice develop pronounced endothelial dysfunction in response to leptin 8. placental ischemia induces elevated leptin and aldosterone levels in pregnant rats. Therefore, we hypothesized that endothelial progesterone receptor activation upregulates ECMR expression which mediates leptin-induced endothelial dysfunction and hypertension in premenopausal and pregnant female mice. Three Specific Aims will rigorously test our hypothesis: 1 (K99): progesterone upregulates endothelial mineralocorticoid receptor expression via endothelial progesterone receptor activation, 2 (K99): endothelial mineralocorticoid receptors mediate leptin-induced endothelial dysfunction and hypertension in female mice, 3 (R00 Independent): leptin-induced, aldosterone-mediated activation of mineralocorticoid receptors contributes to endothelial dysfunction and hypertension in obese preeclampsia. We will utilize novel transgenic mouse models (deficiency of endothelial-specific progesterone receptors and ENaC), endothelial cell culture techniques investigating progesterone-mediated PKC mechanisms and work with experts in the field to determine the regulation and functional relevance of ECMR in leptin- mediated endothelial dysfunction and hypertension in premenopausal females. Furthermore, in the independent phase, we will shift the approach utilizing the reduced uterine perfusion pressure mouse model of placental ischemia to a groundbreaking study of the role of leptin in hypertensive pregnancy. The results of these studies will further our knowledge of sex specific mechanisms of endothelial dysfunction and hypertension in females and may lead to improved treatment strategies for obese pregnant and non-pregnant women. Furthermore, the resources provided by mentors on this application, the environment at Augusta University and the training plan enclosed will advance the applicant toward the goal of transitioning to independent researcher.

项目概要 肥胖的绝经前女性比肥胖男性患血管疾病的风险更高，这表明 肥胖会抵消女性性激素的保护作用，但其潜在机制尚不清楚。 脂肪源性激素瘦素介导肥胖男性和女性的高血压，然而， 机械途径具有性别特异性。临床数据显示女性心血管治疗效果更好 与男性相比，接受盐皮质激素受体（MR）拮抗剂治疗的女性。据此，我们的实验室发表了瘦素- 女性中诱发的高血压和内皮功能障碍是由醛固酮-MR轴介导的。在这个 建议我们提供一些新颖的初步数据： 1. 雌性小鼠对醛固酮更敏感- 诱导内皮功能障碍2.内皮特异性MR（ECMR）缺失和上皮钠通道 (ENaC) 拮抗作用可预防瘦素诱导的女性内皮损伤 3. 女性内皮细胞 小鼠和人类比男性表达更多的 ECMR 4. 卵巢切除术削弱了 ECMR 的表达，但 ECMR 的表达又得以恢复 5. ECMR 表达与骑自行车和怀孕小鼠中的黄体酮水平相关 6. 蛋白质 激酶 C (PKC) 抑制可防止孕酮刺激的 ECMR 表达 7. 怀孕小鼠发育 瘦素 8 引起明显的内皮功能障碍。胎盘缺血导致瘦素升高， 怀孕大鼠的醛固酮水平。因此，我们假设内皮孕酮受体激活 上调 ECMR 表达，介导瘦素诱导的内皮功能障碍和高血压 绝经前和怀孕的雌性小鼠。三个具体目标将严格检验我们的假设：1 (K99)： 黄体酮通过内皮黄体酮上调内皮盐皮质激素受体表达 受体激活，2 (K99)：内皮盐皮质激素受体介导瘦素诱导的内皮细胞 雌性小鼠的功能障碍和高血压，3（R00 独立）：瘦素诱导、醛固酮介导 盐皮质激素受体的激活导致肥胖者的内皮功能障碍和高血压 先兆子痫。我们将利用新型转基因小鼠模型（内皮特异性黄体酮缺乏症） 受体和 ENaC），内皮细胞培养技术研究孕酮介导的 PKC 机制 并与该领域的专家合作，确定 ECMR 在瘦素中的调节和功能相关性 介导绝经前女性的内皮功能障碍和高血压。此外，在独立 阶段，我们将利用降低子宫灌注压的胎盘小鼠模型来改变方法 缺血是瘦素在妊娠高血压中作用的突破性研究。这些研究的结果 将进一步加深我们对女性内皮功能障碍和高血压的性别特异性机制的了解 并可能改善肥胖孕妇和非孕妇的治疗策略。此外， 导师就本申请提供的资源、奥古斯塔大学的环境和培训计划 随附的内容将推动申请人实现过渡为独立研究员的目标。

项目成果

Obesity-associated cardiovascular risk in women: hypertension and heart failure.

女性肥胖相关心血管风险：高血压和心力衰竭。

• 发表时间: 2021
• 作者: Faulkner; Jessica L
• 通讯作者: Jessica L

Mechanisms of leptin-induced endothelial dysfunction.

瘦素诱导的内皮功能障碍的机制。

• 发表时间: 2023-03-01
• 影响因子: 3.2
• 作者: Mellott, Elisabeth;Faulkner, Jessica L
• 通讯作者: Faulkner, Jessica L