Antihypertensive Effect of Food-Origin Isothiocyanate Soluble Epoxide Hydrolase Inhibitors

食品源异硫氰酸酯可溶性环氧化物水解酶抑制剂的抗高血压作用

• 批准号: 10411131
• 负责人: Fawzy Elbarbry
• 金额: $ 12.16万
• 依托单位: PACIFIC UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10411131
• 关键词: Acetylcholinesterase; Acids; Address; Adult; Adverse effects; Affect; Affinity; American; American Heart Association; Angiotensin II; Animal Model; Antihypertensive Agents; Antiinflammatory Effect; Antioxidants; Arachidonic Acids; Binding; Biological Assay; Blood; Blood Pressure; Brassica; Broccoli - dietary; Cabbage - dietary; Cardiovascular Diseases; Cauliflower; Cause of Death; Cessation of life; Chemoprevention; Chronic; Clinical Sciences; Consumption; Coronary artery; Coronary heart disease; Cytochrome P450; Cytosol; Death Rate; Development; Diet; Docking; Doctor of Pharmacy; Dose; Drug Interactions; Drug Kinetics; Effectiveness; Endothelium; Enrollment; Enzymes; Epoxide hydrolase; Epoxy Compounds; Family; Fatty Acids; Female; Fluorescence; Food; Functional disorder; Goals; Healthcare; Horseradish; Human; Hypertension; Inbred SHR Rats; Incidence; Incubated; Individual; Inflammation; Isothiocyanates; Kale - dietary; Kidney; Kinetics; Laboratories; Lepidium sativum; Liver; Measures; Modeling; Molecular; Monophenol Monooxygenase; Morbidity - disease rate; Mustard; Natural Products; Nature; Oral; Oxidative Stress; Pathogenesis; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Phenethyl Isothiocyanate; Plants; Play; Population; Property; Rattus; Readiness; Recombinants; Regulation; Research; Research Infrastructure; Research Training; Resources; Risk; Role; Sodium Chloride; Stroke; Students; Sulforaphane; Testing; Therapeutic; Tissues; Treatment Cost; Uncertainty; Uninsured; United States; Universities; Vegetables; Watercress; allyl isothiocyanate; analog; base; benzyl isothiocyanate; blood pressure reduction; cardiovascular risk factor; cost; cruciferous vegetable; dietary; graduate student; high risk; hypertensive; improved; in vivo; inhibitor; kidney vascular structure; male; minimal risk; mortality; novel; pharmacokinetic characteristic; prevent; side effect; skills; therapeutic target; training opportunity; undergraduate student

PROJECT SUMMARY/ABSTRACT It is estimated that hypertension affects nearly one third of adult Americans (approximately 75 million persons). Unfortunately, whether the hypertension is treated or not, only approximately 50% of adults with hypertension have their blood pressure controlled and therefore have higher risk of cardiovascular morbidity and mortality as well as increased use of health care resources. Hypertension was listed as the leading or contributing cause of death in more than 470,000 Americans in 2019 leading to a death rate of 19.9 per 100,000. In 2012, the calculated total cost of treating hypertension in the US was $51.2 billion and the American Heart Association (AHA) estimates that the total cost of treating hypertension in the US in 2025 will be $225 billion. In the last five years, our laboratory has been investigating newer and safer agents from nature that have the potential to treat and/or protect against hypertension. We have demonstrated that chronic administration of sulforaphane (SF), an isothiocyanate (ITC), to young spontaneously hypertensive rats (SHR) results in preventing the progressive rise in blood pressure in this animal model. The observed antihypertensive effect of the examined ITC was significantly correlated with inhibition of the renal soluble epoxide hydrolase (sEH), a key enzyme in metabolizing endogenously derived fatty acid epoxide and considered an important therapeutic target in a wide range of human cardiovascular diseases. Since ITCs are natural products and rich in the diet, they can provide a viable option for hypertensive patients and prehypertensive individuals who are unable or unwilling to use current antihypertensive agents because of their cost, adverse effects, or risk of drug-drug interactions. These individuals will not only benefit from the potential antihypertensive effect of ITCs, but also receive the documented chemoprevention, antioxidant, and anti-inflammatory effects associated with their use. The objective of this proposal is to study the sEH inhibition and blood pressure lowering effects of several naturally- occurring ITCs, and to identify the structural factors that modulate their effectiveness as sEH inhibitors. The positive impact of this research is to identify potent antihypertensive ITCs with favorable pharmacokinetic properties and affordable cost. Specific Aim 1 will evaluate the potency, selectivity, and mechanism of inhibition of human and rat sEH by ITCs. Specific Aim 2 will investigate the anti-hypertensive effect of the most active ITC compound in SHR. This application offers excellent research training opportunities for undergraduate and graduate students, furthers and strengthens Dr. Elbarbry and his team’s research skills and preparedness for other proposals, and will make significant contributions to the enhancement of the Pacific University’s research infrastructure.

项目总结/摘要 据估计，高血压影响近三分之一的成年美国人（约7500万人）。 不幸的是，无论高血压是否得到治疗，只有大约50%的成年高血压患者 血压得到控制，因此心血管发病率和死亡率风险较高， 增加医疗资源的使用。高血压被列为导致 2019年，超过47万美国人死亡，死亡率为每10万人19.9人。2012年 据计算，美国治疗高血压的总费用为512亿美元，美国心脏协会 (AHA)据估计，到2025年，美国治疗高血压的总成本将达到2250亿美元。在过去五 多年来，我们的实验室一直在研究来自自然界的更新和更安全的药物，这些药物有可能治疗 和/或防止高血压。我们已经证明，长期服用萝卜硫素（SF）， 异硫氰酸酯（ITC），对年轻的自发性高血压大鼠（SHR）的结果，防止进行性上升 在这个动物模型的血压中。观察到的ITC的抗高血压作用是 与肾脏可溶性环氧化物水解酶（sEH）的抑制显著相关，sEH是代谢的关键酶， 内源性衍生的脂肪酸环氧化物，并被认为是广泛的治疗靶点。 人类心血管疾病由于ITC是天然产物并且在饮食中丰富，它们可以提供可行的 对于不能或不愿使用本品的高血压患者和高血压前期个体， 抗高血压药物，因为它们的成本，副作用或药物相互作用的风险。这些 个体不仅将受益于ITC的潜在抗高血压作用， 记录了与其使用相关的化学预防、抗氧化和抗炎作用。的 本提案的目的是研究几种天然- 发生ITCs，并确定调节其作为sEH抑制剂的有效性的结构因素。的 这项研究的积极影响是确定具有良好药代动力学的有效抗高血压ITC 性能和负担得起的成本。具体目标1将评价抑制效力、选择性和机制 人和大鼠sEH的ITCs。具体目标2将研究最活跃的ITC的抗高血压作用 化合物在SHR中的作用。该应用程序为本科生提供了极好的研究培训机会， 研究生，进一步加强和Elbarbry博士和他的团队的研究技能和准备， 其他建议，并将作出重大贡献，以加强太平洋大学的研究 基础设施演进