Luteolin as a therapeutic for hypertension in pregnancy

木犀草素可治疗妊娠期高血压

基本信息

批准号：
10185443
负责人：
Sarosh Rana
金额：
$ 62.64万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10185443
关键词：
Address Affect Angiogenesis Inhibitors Angiogenic Factor Animal Model Arteries Attenuated Back Bioflavonoid Biology Blood Circulation Blood Pressure Blood Vessels Blood flow Cardiovascular system Cell Line Cell model Clinical Trials Complex Data Development Disease Drug usage Endothelial Cells Endothelin-1 Endothelium Epidermal Growth Factor Receptor Etiology Evaluation Functional disorder Health Human Hypertension Hypoxia Inducible Factor In Vitro Inflammation Inflammatory Infusion procedures Interferons Interleukin-1 Interleukin-6 Interleukins Interruption Ischemia Life Link Long-Term Effects Luteolin Maternal Mortality Methodology Modeling Molecular Morbidity - disease rate Nitric Oxide PGF gene Pathogenesis Pathogenicity Pathway interactions Perfusion Peripheral Resistance Pharmacology Pharmacotherapy Phosphotransferases Physiological Placenta Placenta Diseases Play Pre-Eclampsia Pregnancy Pregnant Women Production Proteins Rattus Reactive Oxygen Species Regulation Research Personnel Rodent Model Role Safety Signal Pathway Signal Transduction TNF gene Techniques Testing Therapeutic Therapeutic Agents Tumor Necrosis Factors Uterus Vascular Endothelial Growth Factor Receptor-1 Vascular resistance Vasodilation Woman Work angiogenesis base blood pressure reduction clinically relevant cytokine cytotrophoblast endothelial dysfunction experimental study fetal hemodynamics high throughput screening improved inhibitor/antagonist maternal morbidity mortality novel perinatal morbidity peripheral blood pre-clinical pregnancy disorder pressure protein expression small molecule libraries

项目摘要

PROJECT SUMMARY/ABSTRACT Preeclampsia (PE) is a common and life-threatening hypertensive disorder of pregnancy. This disease affects nearly 7% of all pregnancies and is a leading cause of maternal and fetal morbidity and mortality. There are currently no therapies that treat PE except for early delivery. Data from our lab and others suggest that women with PE have angiogenic imbalance (excess soluble fms-like tyrosine kinase 1 [sFlt1]), evidence of inflammation (excess tumor necrosis factors TNF-α, interleukins such as IFN-𝛾-inducible protein 10-IP-10 and IL-6) and excess reactive oxygen species (ROS). The release of these soluble factors from the placenta into the bloodstream interferes with the supply of pro-angiogenic factors, such as placental growth factor (PlGF), resulting in reduced nitric oxide (NO) and increased endothelin-1 (ET-1), and ultimately endothelial dysfunction and hypertension. The lack of treatment options for PE likely results from its complex etiology and limitations on drug use during pregnancy. Identifying a safe therapeutic for this condition is a major unmet need for the health of pregnant women. The availability of chemical libraries and high-throughput screening methodologies has allowed investigators to discover novel molecules that interfere with signaling pathways involved in disease biology. We screened a chemical library of natural compounds and identified the bioflavonoid, luteolin, as a potent inhibitor of sFlt1 in human placental cell lines and placental explants. In addition, we discovered that luteolin inhibits a variety of pro-inflammatory cytokines (such as IL-1, IL-27, IL-6 and IP-10) and interrupts distinct cellular pathways that inhibit several key proteins implicated in pathogenesis of PE. Specifically, we found the luteolin is a potent inhibitor of hypoxia-inducible factor 1α (HIF-1α, a major regulator of sFlt1). In addition, luteolin reduces TNF- α induced ET-1 production in vitro, reduces blood pressure, relaxes uterine arteries, improves placental perfusion in placental ischemia rat models of PE. Our exciting and novel preliminary data led us to propose the central hypothesis that luteolin improves uterine perfusion and reduces total peripheral resistance and blood pressure in models of PE by reducing placental production of sFlt1 and HIF-1α and inhibiting cytokines such as IP-10 and TNF α. In addition, we propose that luteolin decreases blood pressure by inhibiting TNF-α and sFlt1-induced endothelial production of ET-1. To test this hypothesis, we will use human placental explants, cytotrophoblast cell lines, cultured endothelial cells, isolated blood vessels, as well as molecular, pharmacological and physiological techniques in novel animal models of PE, the Reduction in Uterine Perfusion Pressure (RUPP) model and the sFlt1 model. Our specific aims and central hypothesis are backed by strong preliminary and feasibility data. The proposed experiments will identify mechanisms by which luteolin interferes with the pathophysiological pathways linking placental ischemia with maternal cardiovascular dysfunction, while generating preclinical data to support the development of luteolin as a therapy for PE.

项目概要/摘要先兆子痫（PE）是一种常见且危及生命的妊娠期高血压疾病。占所有妊娠的近 7%，是孕产妇和胎儿发病和死亡的主要原因。目前，除了早产之外，没有其他治疗方法可以治疗早产。 PE 患者存在血管生成失衡（过量可溶性 fms 样酪氨酸激酶 1 [sFlt1]）、炎症证据（过量的肿瘤坏死因子TNF-α、白细胞介素如IFN-β诱导蛋白10-IP-10和IL-6）和过量的活性氧（ROS）从胎盘释放到胎盘中。血流干扰促血管生成因子的供应，例如胎盘生长因子（PlGF），导致一氧化氮（NO）减少和内皮素-1（ET-1）增加，最终导致内皮功能障碍和高血压缺乏治疗选择可能是由于其复杂的病因和药物的限制。确定针对这种情况的安全治疗方法是未满足的健康需求。化学库和高通量筛选方法的可用性允许孕妇。研究人员发现干扰疾病生物学信号通路的新分子。筛选了天然化合物的化学文库，并鉴定出生物类黄酮、木犀草素是一种有效的抑制剂此外，我们还发现木犀草素可抑制人胎盘细胞系和胎盘外植体中的 sFlt1。多种促炎细胞因子（如 IL-1、IL-27、IL-6 和 IP-10）并干扰不同的细胞具体而言，我们发现木犀草素是抑制与 PE 发病机制有关的几种关键蛋白的途径。缺氧诱导因子 1α（HIF-1α，sFlt1 的主要调节因子）的有效抑制剂。此外，木犀草素还可降低缺氧诱导因子 1α 的活性。 TNF-α 在体外诱导 ET-1 产生，降低血压，舒张子宫动脉，改善胎盘我们激动人心且新颖的初步数据使我们提出了胎盘缺血大鼠模型的灌注。中心假设是木犀草素改善子宫灌注并降低总外周阻力通过减少胎盘 sFlt1 和 HIF-1α 的产生并抑制此外，我们认为木犀草素还可以降低血压。抑制 TNF-α 和 sFlt1 诱导的内皮细胞产生 ET-1 为了检验这一假设，我们将使用。人胎盘外植体、细胞滋养层细胞系、培养的内皮细胞、分离的血管以及作为PE新动物模型中的分子、药理学和生理学技术，减少子宫灌注压 (RUPP) 模型和 sFlt1 模型我们的具体目标和中心假设是。拟议的实验将得到强有力的初步和可行性数据的支持。木犀草素干扰胎盘缺血与母体心血管之间的病理生理学途径功能障碍，同时生成临床前数据以支持木犀草素作为 PE 疗法的开发。