Dipartimento di Scienze Biomediche Avanzate, Università FEDERICO II, 80131 Napoli, Italy.
Unità Operativa Complessa Cardiologia con UTIC ed Emodinamica-Dipartimento Emergenza Accettazione, Azienda Ospedaliera "Antonio Cardarelli", 80131 Napoli, Italy.
Cells. 2020 Sep 21;9(9):2134. doi: 10.3390/cells9092134.
During the last three decades, timely myocardial reperfusion using either thrombolytic therapy or primary percutaneous intervention (pPCI) has allowed amazing improvements in outcomes with a more than halving in 1-year ST-elevation myocardial infarction (STEMI) mortality. However, mortality and left ventricle (LV) remodeling remain substantial in these patients. As such, novel therapeutic interventions are required to reduce myocardial infarction size, preserve LV systolic function, and improve survival in reperfused-STEMI patients. Myocardial ischemia-reperfusion injury (MIRI) prevention represents the main goal to reach in order to reduce STEMI mortality. There is currently no effective therapy for MIRI prevention in STEMI patients. A significant reason for the weak and inconsistent results obtained in this field may be the presence of multiple, partially redundant, mechanisms of cell death during ischemia-reperfusion, whose relative importance may depend on the conditions. Therefore, it is always more recognized that it is important to consider a "multi-targeted cardioprotective therapy", defined as an additive or synergistic cardioprotective agents or interventions directed to distinct targets with different timing of application (before, during, or after pPCI). Given that some neprilysin (NEP) substrates (natriuretic peptides, angiotensin II, bradykinin, apelins, substance P, and adrenomedullin) exert a cardioprotective effect against ischemia-reperfusion injury, it is conceivable that antagonism of proteolytic activity by this enzyme may be considered in a multi-targeted strategy for MIRI prevention. In this review, by starting from main pathophysiological mechanisms promoting MIRI, we discuss cardioprotective effects of NEP substrates and the potential benefit of NEP pharmacological inhibition in MIRI prevention.
在过去的三十年中，通过溶栓治疗或直接经皮冠状动脉介入治疗（pPCI）进行及时的心肌再灌注，使 ST 段抬高型心肌梗死（STEMI）患者的 1 年死亡率降低了一半以上，这使得治疗效果有了惊人的改善。然而，这些患者的死亡率和左心室（LV）重构仍然很高。因此，需要新的治疗干预措施来减少心肌梗死面积，保持 LV 收缩功能，并改善再灌注治疗后的 STEMI 患者的生存率。预防心肌缺血再灌注损伤（MIRI）是降低 STEMI 死亡率的主要目标。目前，对于 STEMI 患者，还没有有效的 MIRI 预防治疗方法。在该领域获得的结果较弱且不一致的一个重要原因可能是在缺血再灌注过程中存在多种、部分冗余的细胞死亡机制，其相对重要性可能取决于具体情况。因此，人们越来越认识到，考虑一种“多靶点心脏保护治疗”很重要，这种治疗方法定义为针对不同靶点的具有不同应用时机（pPCI 之前、期间或之后）的加性或协同性心脏保护剂或干预措施。鉴于一些 Neprilysin（NEP）底物（利钠肽、血管紧张素 II、缓激肽、阿佩林、P 物质和肾上腺髓质素）对缺血再灌注损伤具有心脏保护作用，可以想象，通过这种酶的拮抗其蛋白水解活性可能被认为是 MIRI 预防的多靶点策略之一。在这篇综述中，我们从促进 MIRI 的主要病理生理机制开始，讨论了 NEP 底物的心脏保护作用以及 NEP 药理学抑制在 MIRI 预防中的潜在益处。
