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: 10381770
• 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/10381770
• 关键词: Adipose tissue; Adrenal Glands; Aldosterone; Animal Model; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cell Culture Techniques; 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; Investigative Techniques; Ischemia; Knowledge; Lead; Leptin; Mediating; Mediator of activation protein; Mentors; Mineralocorticoid Receptor; Molecular; Mus; Myocardial Infarction; Obesity; Obesity Epidemic; Obesity associated cardiovascular disease; Outcome; Ovariectomy; Pathway interactions; Perfusion; Pharmacologic Substance; Pharmacology; 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; cardiovascular risk factor; efficacious treatment; endothelial dysfunction; epithelial Na+ channel; female sex hormone; field study; human tissue; improved; male; men; mouse model; novel; obesity prevention; 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.

项目摘要 肥胖的绝经前妇女患血管疾病的风险高于肥胖男性 肥胖否定了女性性激素的保护作用，但是，潜在的机制尚不清楚。 脂肪衍生的激素瘦素介导肥胖的雄性和女性的高血压，但是 机械途径是性别特定的。临床数据报告女性的心血管治疗结果更好 用矿物皮质激素受体（MR）拮抗剂治疗的拮抗剂比男性治疗。根据，我们的实验室发表了瘦素 - 诱导的高血压和内皮功能障碍是由女性醛固酮-MR轴介导的。在这个 提案我们提供了许多新型的初步数据：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）拮抗作用阻止瘦素诱导的女性内皮损伤3。女性的内皮细胞 小鼠和人类表达的ECMR比男性4。卵巢切除术钝性ECMR表达，该表达已恢复 孕酮5。ECMR表达与循环和孕妇小鼠中的孕酮水平相关6。 激酶C（PKC）抑制可防止孕激素刺激的ECMR表达7。 响应瘦素8的明显内皮功能障碍。胎盘缺血会诱导瘦素升高和 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）： 孕酮上调通过内皮孕酮表达内皮矿物皮质激素受体的表达 受体激活，2（K99）：内皮矿物皮质激素受体介导瘦素诱导的内皮 雌性小鼠的功能障碍和高血压，3（R00独立）：瘦素诱导的醛固酮介导的 矿物皮质激素受体的激活有助于肥胖的内皮功能障碍和高血压 子痫前期。我们将利用新型的转基因小鼠模型（内皮特异性孕酮的缺乏 受体和ENAC），研究孕激素介导的PKC机制的内皮细胞培养技术 并与该领域的专家合作，以确定ECMR在瘦素中的调节和功能相关性 绝经前女性中介导的内皮功能障碍和高血压。此外，在独立 阶段，我们将利用胎盘的子宫灌注压力小鼠模型移动该方法 缺血，对瘦素在高血压妊娠中的作用进行了开创性的研究。这些研究的结果 将进一步了解我们对女性内皮功能障碍和高血压的性别特定机制的了解 并可能导致改善肥胖孕妇和非怀孕妇女的治疗策略。此外， 导师提供的有关此应用程序的资源，奥古斯塔大学的环境和培训计划 封闭式将使申请人朝着过渡到独立研究人员的目标。