{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:28:34Z","timestamp":1774916914563,"version":"3.50.1"},"reference-count":220,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,9,21]],"date-time":"2020-09-21T00:00:00Z","timestamp":1600646400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007195","name":"Universit\u00e0 degli Studi di Napoli Federico II","doi-asserted-by":"publisher","award":["CardioPaTh PhD programme"],"award-info":[{"award-number":["CardioPaTh PhD programme"]}],"id":[{"id":"10.13039\/100007195","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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 \u201cmulti-targeted cardioprotective therapy\u201d, 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.<\/jats:p>","DOI":"10.3390\/cells9092134","type":"journal-article","created":{"date-parts":[[2020,9,21]],"date-time":"2020-09-21T21:01:21Z","timestamp":1600722081000},"page":"2134","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["The Rationale of Neprilysin Inhibition in Prevention of Myocardial Ischemia-Reperfusion Injury during ST-Elevation Myocardial Infarction"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3476-5696","authenticated-orcid":false,"given":"Alessandro","family":"Bellis","sequence":"first","affiliation":[{"name":"Dipartimento di Scienze Biomediche Avanzate, Universit\u00e0 FEDERICO II, 80131 Napoli, Italy"},{"name":"Unit\u00e0 Operativa Complessa Cardiologia con UTIC ed Emodinamica\u2014Dipartimento Emergenza Accettazione, Azienda Ospedaliera \u201cAntonio Cardarelli\u201d, 80131 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ciro","family":"Mauro","sequence":"additional","affiliation":[{"name":"Unit\u00e0 Operativa Complessa Cardiologia con UTIC ed Emodinamica\u2014Dipartimento Emergenza Accettazione, Azienda Ospedaliera \u201cAntonio Cardarelli\u201d, 80131 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emanuele","family":"Barbato","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Biomediche Avanzate, Universit\u00e0 FEDERICO II, 80131 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3297-8399","authenticated-orcid":false,"given":"Giuseppe","family":"Di Gioia","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Biomediche Avanzate, Universit\u00e0 FEDERICO II, 80131 Napoli, Italy"},{"name":"Cardiac Catheterization Laboratory, Montevergine Clinic, 83013 Mercogliano (AV), Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1599-4509","authenticated-orcid":false,"given":"Daniela","family":"Sorriento","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Biomediche Avanzate, Universit\u00e0 FEDERICO II, 80131 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0701-6449","authenticated-orcid":false,"given":"Bruno","family":"Trimarco","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Biomediche Avanzate, Universit\u00e0 FEDERICO II, 80131 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2158-6317","authenticated-orcid":false,"given":"Carmine","family":"Morisco","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Biomediche Avanzate, Universit\u00e0 FEDERICO II, 80131 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1772","DOI":"10.1016\/j.amjcard.2011.01.066","article-title":"Usefulness of satisfactory control of low-density lipoprotein cholesterol to predict left ventricular remodeling after a first ST-elevation myocardial infarction successfully reperfused","volume":"107","author":"Buono","year":"2011","journal-title":"Am. 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