Antihypertensive Effect of Food-Origin Isothiocyanate Soluble Epoxide Hydrolase Inhibitors

项目摘要/摘要 据估计，近三分之一的美国成年人(约7500万人)患有高血压。 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，因此患心血管疾病和死亡的风险更高 以及增加卫生保健资源的使用。高血压被列为主要或促成的原因 2019年，超过47万美国人死亡，死亡率为每10万人中有19.9人死亡。2012年， 美国治疗高血压的计算总成本为512亿美元，美国心脏协会 美国心脏病协会(AHA)估计，2025年美国治疗高血压的总成本将达到225亿美元。在过去的五年中 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 和/或预防高血压。我们已经证明，长期服用萝卜硫素(SF)，以及 异硫氰酸盐(ITC)对幼年自发性高血压大鼠(SHR)的抑制作用 在这个动物模型中对血压有影响。被检查的ITC的降压效果观察到 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 内源性脂肪酸环氧化物，被认为是一种重要的治疗靶点 人类心血管疾病。由于ITCs是天然产品，而且含有丰富的饮食，它们可以提供一种可行的 不能或不愿使用Current的高血压患者和高血压前期患者的选择 抗高血压药物，因为其成本、不良反应或药物相互作用的风险。这些 个人不仅将受益于ITCs潜在的降压作用，而且还将获得 记录了与其使用相关的化学预防、抗氧化剂和抗炎作用。这个 本建议的目的是研究几种天然药物对sEH的抑制和降压作用。 并确定影响其作为sEH抑制剂的有效性的结构性因素。这个 这项研究的积极影响是发现具有良好药代动力学的有效降压ITCs 物业和负担得起的成本。特定目标1将评估抑制的效力、选择性和机制 ITCS对人和大鼠的SSH进行检测。《特殊目的2》将研究最活跃的ITC的降压作用 SHR中的化合物。本申请为本科生和学生提供了极好的科研培训机会 研究生，进一步和加强埃尔巴布里博士和他的团队的研究技能和准备 其他建议，并将为加强太平洋大学的研究做出重大贡献 基础设施。

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.