Maiocchi Sophie L, Ku Jacqueline, Thai Thuan, Chan Enoch, Rees Martin D, Thomas Shane R
Mechanisms of Disease and Translational Research Unit, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Australia; Department of Surgery, Centre for Nanotechnology in Drug Delivery, University of North Carolina at Chapel Hill, USA.
Mechanisms of Disease and Translational Research Unit, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Australia.
Pharmacol Ther. 2021 May;221:107711. doi: 10.1016/j.pharmthera.2020.107711. Epub 2020 Oct 31.
Myeloperoxidase (MPO) is a prominent mammalian heme peroxidase and a fundamental component of the innate immune response against microbial pathogens. In recent times, MPO has received considerable attention as a key oxidative enzyme capable of impairing the bioactivity of nitric oxide (NO) and promoting endothelial dysfunction; a clinically relevant event that manifests throughout the development of inflammatory cardiovascular disease. Increasing evidence indicates that during cardiovascular disease, MPO is released intravascularly by activated leukocytes resulting in its transport and sequestration within the vascular endothelium. At this site, MPO catalyzes various oxidative reactions that are capable of promoting vascular inflammation and impairing NO bioactivity and endothelial function. In particular, MPO catalyzes the production of the potent oxidant hypochlorous acid (HOCl) and the catalytic consumption of NO via the enzyme's NO oxidase activity. An emerging paradigm is the ability of MPO to also influence endothelial function via non-catalytic, cytokine-like activities. In this review article we discuss the implications of our increasing knowledge of the versatility of MPO's actions as a mediator of cardiovascular disease and endothelial dysfunction for the development of new pharmacological agents capable of effectively combating MPO's pathogenic activities. More specifically, we will (i) discuss the various transport mechanisms by which MPO accumulates into the endothelium of inflamed or diseased arteries, (ii) detail the clinical and basic scientific evidence identifying MPO as a significant cause of endothelial dysfunction and cardiovascular disease, (iii) provide an up-to-date coverage on the different oxidative mechanisms by which MPO can impair endothelial function during cardiovascular disease including an evaluation of the contributions of MPO-catalyzed HOCl production and NO oxidation, and (iv) outline the novel non-enzymatic mechanisms of MPO and their potential contribution to endothelial dysfunction. Finally, we deliver a detailed appraisal of the different pharmacological strategies available for targeting the catalytic and non-catalytic modes-of-action of MPO in order to protect against endothelial dysfunction in cardiovascular disease.
髓过氧化物酶（MPO）是一种重要的哺乳动物血红素过氧化物酶，是针对微生物病原体的固有免疫反应的基本组成部分。近年来，MPO作为一种关键的氧化酶受到了相当多的关注，它能够损害一氧化氮（NO）的生物活性并促进内皮功能障碍，这是一种在炎症性心血管疾病发展过程中出现的临床相关事件。越来越多的证据表明，在心血管疾病期间，MPO由活化的白细胞释放到血管内，导致其在血管内皮中运输和潴留。在这个部位，MPO催化各种氧化反应，能够促进血管炎症并损害NO生物活性和内皮功能。特别是，MPO催化产生强氧化剂次氯酸（HOCl），并通过该酶的NO氧化酶活性催化消耗NO。一个新出现的模式是MPO还能够通过非催化、细胞因子样活性影响内皮功能。在这篇综述文章中，我们讨论了我们对MPO作为心血管疾病和内皮功能障碍介质的多种作用的认识不断增加，这对开发能够有效对抗MPO致病活性的新型药物的影响。更具体地说，我们将（i）讨论MPO积聚到发炎或患病动脉内皮中的各种运输机制，（ii）详细阐述将MPO确定为内皮功能障碍和心血管疾病重要原因的临床和基础科学证据，（iii）提供关于MPO在心血管疾病期间损害内皮功能的不同氧化机制的最新报道，包括对MPO催化产生HOCl和NO氧化作用的评估，以及（iv）概述MPO的新型非酶机制及其对内皮功能障碍的潜在贡献。最后，我们详细评估了针对MPO的催化和非催化作用模式的不同药理策略，以预防心血管疾病中的内皮功能障碍。
