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先天免疫反应的基本组成部分。近年来，MPO作为一种能够损害一氧化氮（NO）的生物活性并促进内皮功能障碍的关键氧化酶受到了广泛关注。在炎症性心血管疾病的整个发展过程中表现出来的临床相关事件。越来越多的证据表明，在心血管疾病期间，MPO 由活化的白细胞在血管内释放，导致其在血管内皮内转运和隔离。在该部位，MPO 催化各种能够促进血管炎症并损害 NO 生物活性和内皮功能的氧化反应。特别是，MPO 通过酶的 NO 氧化酶活性催化强氧化剂次氯酸 (HOCl) 的产生和 NO 的催化消耗。一种新兴的范式是 MPO 也能够通过非催化的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的介质的多功能性的了解越来越多，这对开发能够有效对抗 MPO 致病活性的新药理学试剂的意义。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转运机制，(ii) 详细说明 MPO 是导致内皮功能障碍和心血管疾病的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，包括评估 MPO 催化的 HOCl 产生和 NO 氧化的贡献，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，我们详细评估了可用于靶向 MPO 的催化和非催化作用模式的不同药理学策略，以防止心血管疾病中的内皮功能障碍。(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，包括评估 MPO 催化的 HOCl 产生和 NO 氧化的贡献，以及 (iv) 概述新型非-MPO 的酶促机制及其对内皮功能障碍的潜在贡献。最后，我们详细评估了可用于靶向 MPO 的催化和非催化作用模式的不同药理学策略，以防止心血管疾病中的内皮功能障碍。(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，包括评估 MPO 催化的 HOCl 产生和 NO 氧化的贡献，以及 (iv) 概述新型非-MPO 的酶促机制及其对内皮功能障碍的潜在贡献。最后，我们详细评估了可用于靶向 MPO 的催化和非催化作用模式的不同药理学策略，以防止心血管疾病中的内皮功能障碍。(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，我们详细评估了可用于靶向 MPO 的催化和非催化作用模式的不同药理学策略，以防止心血管疾病中的内皮功能障碍。