The Rationale of Neprilysin Inhibition in Prevention of Myocardial Ischemia-Reperfusion Injury during ST-Elevation Myocardial Infarction

Abstract

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.

ARNI versus ACEI/ARB in Reducing Cardiovascular Outcomes after Myocardial Infarction

“…Recently, the application of ARNI for reversing cardiac remodelling has attracted a great deal of attention. Sacubitril/valsartan simultaneously blocks the effects of the angiotensin type 1 receptor through valsartan and inhibits the breakdown of several vasoactive peptides that are degraded by neprilysin 19 . Meta‐analysis also indicates that ARNI can improve functional capacity and cardiac reverse remodelling in HFrEF patients compared with ACEI/ARB 20 .…”

Sevoflurane Alleviates Myocardial Ischemia Reperfusion Injury by Inhibiting P2X7-NLRP3 Mediated Pyroptosis

“…Apoptosis is an energy-dependent process and could be induced during ischemia which is affected by reperfusion (when oxygen supply is reinitiated) ( Bellis et al, 2020 ). The apoptosis of cardiomyocytes is the main form of ischemia-reperfusion injury and the cytological basis for the occurrence and evolution of many cardiovascular diseases.…”

Network Pharmacology-Based Investigation and Experimental Exploration of the Antiapoptotic Mechanism of Colchicine on Myocardial Ischemia Reperfusion Injury

“…Nevertheless, there are few effective drugs for the treatment of MIRI clinically. Therefore, finding a resultful drug to treat MIRI makes sense ( Bellis et al, 2020 ). Network pharmacology is an emerging discipline based on systems biology, which is used to analyze biological system networks to select specific signal nodes, so that the potential interaction between drugs and targets can be accurately determined ( Barabasi et al, 2011 ; Zhao et al, 2016 ).…”