Luteolin as a therapeutic for hypertension in pregnancy

木犀草素可治疗妊娠期高血压

• 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
• 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

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.

项目摘要/摘要 防护（PE）是一种常见且威胁生命的高血压疾病。这种疾病会影响 近7％的怀孕是母亲和胎儿发病率和死亡率的主要原因。有 目前尚无治疗PE的疗法，除了提早分娩。我们实验室和其他人的数据表明女性 PE具有血管生成失衡（过量的固体FMS样酪氨酸激酶1 [SFLT1]），炎症的证据 （多余的肿瘤坏死因子TNF-α，白细胞介绍，例如IFN-𝛾诱导蛋白10-IP-10和IL-6）和IL-6）和 过量的活性氧（ROS）。这些固体因素从plapeta释放到 血液干扰促血管生成因子的供应，例如位置生长因子（PLGF），导致 在减少一氧化氮（NO）和内皮素-1（ET-1）的增加中，最终的内皮功能障碍和 高血压。缺乏PE的治疗选择可能是由于其复杂的病因和对药物的局限性导致的 怀孕期间使用。确定这种情况的安全疗法是对健康的主要需求 孕妇。化学库的可用性和高通量筛选方法已允许 研究人员发现新的分子会干扰疾病生物学涉及的信号通路。我们 筛选了天然化合物的化学库，并确定了生物黄酮叶黄素素为有效的抑制剂 人类位置细胞系和斑点外植体中的sflt1。此外，我们发现叶黄素抑制了 多种促炎细胞因子（例如IL-1，IL-27，IL-6和IP-10），并中断不同的细胞 抑制PE发病机理实现的几种关键蛋白的途径。具体来说，我们发现叶黄素是 低氧诱导因子1α的潜在抑制剂（HIF-1α，SFLT1的主要调节剂）。另外，黄体蛋白还原 TNF-α在体外诱导的ET-1产生，降低血压，放松子宫动脉，改善位置 PE的占地缺血大鼠模型中的灌注。我们令人兴奋和新颖的初步数据使我们提出了 中心假设，即叶黄素可以改善子宫灌注并降低总周围耐药性和 PE模型中的血压通过减少SFLT1和HIF-1α的位置产生并抑制 IP-10和TNFα等细胞因子。此外，我们建议叶黄素降低血压 抑制TNF-α和SFLT1诱导的ET-1的内皮产生。为了检验这一假设，我们将使用 人胎盘外植体，细胞增生细胞细胞系，培养的内皮细胞，孤立的血管 作为分子，新型动物模型中的药物和物理技术，降低 子宫灌注压力（RUPP）模型和SFLT1模型。我们的具体目标和中心假设是 以强大的初步和可行性数据支持。提出的实验将确定通过 黄体素干扰与母体心血管联系的病理生理途径 功能障碍，同时生成临床前数据以支持Luteolin作为PE的疗法的发展。