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

基本信息

批准号：
10706992
负责人：
Fawzy Elbarbry
金额：
$ 12.2万
依托单位：
PACIFIC UNIVERSITY
依托单位国家：
美国
项目类别：
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/10706992
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 Arteries Binding Biological Assay Biological Availability Blood Pressure Brassica Broccoli - dietary Cabbage - dietary Cardiovascular Diseases Cauliflower Cause of Death Central Nervous System Cessation of life Chemoprevention Chronic Clinical Sciences Consumption 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 Heart 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 Phenethyl Isothiocyanate Plants Play Population Probability 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 benzyl isothiocyanate blood pressure elevation 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 pharmacologic prevent side effect skills structural determinants therapeutic target training opportunity undergraduate student

项目摘要

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.

项目概要/摘要据估计，高血压影响着近三分之一的美国成年人（约 7500 万人）。不幸的是，无论高血压是否得到治疗，只有大约 50% 的成年人患有高血压血压得到控制，因此心血管疾病发病和死亡的风险较高以及医疗保健资源的使用增加被列为导致高血压的主要原因。 2019 年，超过 47 万美国人死亡，2012 年死亡率为每 10 万人 19.9 人。美国治疗高血压的总费用为 512 亿美元，美国心脏协会美国心脏协会 (AHA) 估计，到 2025 年，美国治疗高血压的总费用将在过去 5 年达到 2250 亿美元。多年来，我们的实验室一直在研究来自大自然的更新、更安全的药物，这些药物有可能治疗我们已经证明，长期服用萝卜硫素（SF）是一种预防高血压的药物。异硫氰酸盐（ITC）对年轻的自发性高血压大鼠（SHR）可防止其进行性升高在该动物模型中观察到的 ITC 的抗高血压作用是与肾可溶性环氧化物水解酶（sEH）的抑制显着相关，sEH是代谢中的关键酶内源性衍生的脂肪酸环氧化物，被认为是多种疾病的重要治疗靶点由于ITCs是天然产物并且富含在饮食中，因此它们可以为人类心血管疾病提供可行的治疗方法。无法或不愿意使用当前药物的高血压患者和高血压前期人士的选择由于其成本、不良反应或药物间相互作用的风险而选择抗高血压药物。个人不仅会受益于 ITC 的潜在降压作用，而且还会获得记录了与其使用相关的化学预防、抗氧化和抗炎作用。本提案的目的是研究几种天然物质的 sEH 抑制和降血压作用 ITC，并确定调节其作为 sEH 抑制剂有效性的结构因素。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 具体目标 1 将评估抑制的效力、选择性和机制。具体目标 2 将研究最活跃的 ITC 的抗高血压作用。该应用程序为本科生和学生提供了极好的研究培训机会。研究生，进一步加强了 Elbarbry 博士及其团队的研究技能和准备工作其他提案，将为加强太平洋大学的研究做出重大贡献基础设施。