Antihypertensive Effect of Food-Origin Isothiocyanate Soluble Epoxide Hydrolase Inhibitors

点击翻译按钮获取中文摘要

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.