Department of Medicinal Chemistry, University of Washington, Seattle, WA, United States.
Department of Pharmaceutics, University of Washington, Seattle, WA, United States.
Adv Pharmacol. 2023;97:201-227. doi: 10.1016/bs.apha.2023.02.001. Epub 2023 Mar 27.
The seminal discovery that cytochrome P450 enzymes (CYPs) can oxidize polyunsaturated fatty acids (PUFAs) sparked a new area of research aimed at discovering the role of these metabolites in cardiac physiology and pathophysiology. CYPs metabolize arachidonic acid, an ω-6 PUFA, to alcohols and epoxides with the latter providing cardioprotection following myocardial infarction, hypertrophy, and diabetes-induced cardiomyopathy through their anti-inflammatory, vasodilatory and antioxidant properties. Despite their protective properties, the use of EETs as therapeutic agents is hampered mainly by their rapid hydrolysis to less active vicinal diols by soluble epoxide hydrolase (sEH). Several approaches have been investigated to prolong EET signaling effects using small molecule sEH inhibitors, chemically and biologically stable analogs of EETs and more recently, through the development of an sEH vaccine. Alternatively, research investigating the cardioprotective outcomes of ω-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), mainly focused on dietary intake or supplementation studies. EPA and DHA have overlapping but distinct effects on myocardial function and merit separate studies to fully understand their mechanism of cardiac protection. In contrast to EETs, relatively fewer studies examined the protective mechanisms of EPA and DHA derived epoxides to determine if some protective effects are in part due to the CYP mediated downstream metabolites. The actions of CYPs on PUFAs generate potent oxylipins utilizing diverse cardioprotective mechanisms and the extent of their full potential will be important for the future development of therapeutics to prevent or treat cardiovascular disease.
细胞色素 P450 酶（CYPs）可以氧化多不饱和脂肪酸（PUFAs）这一开创性发现激发了一个新的研究领域，旨在发现这些代谢物在心脏生理学和病理生理学中的作用。CYPs 代谢花生四烯酸，一种 ω-6 PUFAs，生成醇和环氧化物，后者通过其抗炎、血管扩张和抗氧化特性，为心肌梗死、肥大和糖尿病性心肌病后提供心脏保护。尽管具有保护作用，但 EETs 作为治疗剂的应用主要受到其通过可溶性环氧化物水解酶（sEH）迅速水解为活性较低的毗邻二醇的限制。已经研究了几种方法来延长 EET 信号作用，包括使用小分子 sEH 抑制剂、EETs 的化学和生物稳定类似物，以及最近通过开发 sEH 疫苗。或者，研究 ω-3 PUFAs、二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）的心脏保护作用的研究主要集中在饮食摄入或补充研究上。EPA 和 DHA 对心肌功能有重叠但不同的影响，值得进行单独的研究，以充分了解它们的心脏保护机制。与 EETs 相比，相对较少的研究检查了 EPA 和 DHA 衍生的环氧化物的保护机制，以确定一些保护作用是否部分归因于 CYP 介导的下游代谢物。CYPs 对 PUFAs 的作用会产生利用多种心脏保护机制的强效氧化脂类，其全部潜力的程度对于未来开发预防或治疗心血管疾病的治疗方法将非常重要。
