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: 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
• 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

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.

项目摘要/摘要 据估计，高血压影响了几乎三分之一的成年美国人（约7500万人）。 不幸的是，是否治疗高血压，大约有50％的高血压成年人 控制血压，因此具有更高的心血管发病率和死亡的风险 以及增加医疗资源的使用。高血压被列为 2019年，超过470,000名美国人的死亡导致死亡率为19.9每10万。 2012年 美国治疗高血压的总成本为512亿美元，美国心脏协会 （aha）估计，2025年美国治疗高血压的总成本将为2250亿美元。在最后五个 多年来，我们的实验室一直在调查来自自然的新型和安全的代理商，这些代理有可能治疗 和/或防止高血压。我们已经证明了长期给予磺胺硫烷（SF） 异硫氰酸盐（ITC），对年轻的赞助高血压大鼠（SHR）导致渐进式上升 在该动物模型中的血压中。观察到的ITC的降压作用是 与抑制肾脏固体环氧化物水解酶（SEH）的抑制显着相关，这是代谢中的键酶 内源性衍生的脂肪酸环氧化物，并将其视为一个重要的治疗靶标 人类心血管疾病。由于ITC是天然产品，并且饮食丰富，因此可以提供可行的 高血压患者和无法或不愿使用当前的高血压前患者的选择 降压药因其成本，不利影响或药物相互作用的风险。这些 个人不仅将从ITC的潜在降压作用中受益，而且还会受益 与使用相关的化学预防，抗氧化剂和抗炎作用。这 该提案的目的是研究几种自然的SEH抑制和血压降低效应 发生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潜在降压ITC 财产和负担得起的成本。特定目标1将评估抑制的效力，选择性和机制 ITC的人类和老鼠SEH。特定的目标2将研究最活跃的ITC的抗高血压效应 SHR中的化合物。该应用程序为本科生提供了极好的研究培训机会 研究生，进一步和优势Elbarbry博士及其团队的研究技能和准备 其他建议，将为太平洋大学的研究做出重大贡献 基础设施。