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 子痫前期(PE)是一种常见的、危及生命的妊娠高血压疾病。这种病影响 约占所有妊娠的7%，是孕产妇和胎儿发病率和死亡率的主要原因。确实有 目前，除了早产外，还没有治疗PE的方法。来自我们实验室和其他实验室的数据表明，女性 PE有血管生成失衡(过量的可溶性FMS样酪氨酸激酶1[sFlt1])，炎症的证据 (过量的肿瘤坏死因子肿瘤坏死因子-α、白细胞介素如干扰素-𝛾诱导蛋白10-IP-10和IL-6)和 过量的活性氧(ROS)。这些可溶性因子从胎盘释放到胎盘 血流干扰促血管生成因子的供应，如胎盘生长因子(PlGF)，导致 在减少的一氧化氮(NO)和升高的内皮素-1(ET-1)，最终导致内皮功能障碍和 高血压。PE缺乏治疗选择可能是由于其复杂的病因和药物的限制 在怀孕期间使用。为这种疾病寻找安全的治疗方法是一项尚未得到满足的健康需求 怀孕的女人。化学库和高通量筛选方法的可用性使 研究人员发现干扰涉及疾病生物学的信号通路的新分子。我们 筛选了天然化合物的化学库，并确定生物黄酮类化合物木犀草素是一种有效的抑制剂。 人胎盘细胞系和胎盘外植体中sFlt1的表达。此外，我们发现木犀草素抑制一种 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 抑制在PE发病机制中涉及的几个关键蛋白的通路。具体来说，我们发现木犀草素 缺氧诱导因子1α的有效抑制物(HIF-1α，sFlt1的主要调节因子)。此外，木犀草素还能减少 肿瘤坏死因子-α体外诱导ET-1的产生，降低血压，松弛子宫动脉，改善胎盘 胎盘缺血大鼠PE模型的血流灌注。我们令人兴奋和新奇的初步数据使我们提出了 中心假说木犀草素改善子宫血流灌注并降低总外周阻力和 减少胎盘sFlt1和HIF-1α的产生及抑制对PE模型血压的影响 IP-10、肿瘤坏死因子α等细胞因子。此外，我们建议木犀草素通过以下方式降低血压 抑制肿瘤坏死因子-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，以及分离的血管 随着分子、药理学和生理学技术在新的PE动物模型中的应用， 子宫灌流压力(RUPP)模型和sFlt1模型。我们的具体目标和中心假设是 有强劲的初步和可行性数据支持。拟议的实验将确定通过哪些机制 木犀草素干扰胎盘缺血与母体心血管的病理生理通路 功能障碍，同时产生临床前数据，支持木犀草素作为PE治疗方法的开发。