{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T02:25:46Z","timestamp":1781663146221,"version":"3.54.5"},"reference-count":36,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2021,8,10]],"date-time":"2021-08-10T00:00:00Z","timestamp":1628553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2019R1I1A2A01060702"],"award-info":[{"award-number":["2019R1I1A2A01060702"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003710","name":"Korea Health Industry Development Institute","doi-asserted-by":"publisher","award":["HR20C0026"],"award-info":[{"award-number":["HR20C0026"]}],"id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005006","name":"Asan Institute for Life Sciences, Asan Medical Center","doi-asserted-by":"publisher","award":["2019IP-0823, 2020IP-0086"],"award-info":[{"award-number":["2019IP-0823, 2020IP-0086"]}],"id":[{"id":"10.13039\/501100005006","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Angiotensin receptor neprilysin inhibitor (ARNI) treatment reduces functional mitral regurgitation (MR) to a greater extent than angiotensin receptor blocker (ARB) treatment alone, but the mechanism is unclear. We evaluated the mechanisms of how ARNI has an effect on functional MR. After inducing functional MR by left circumflex coronary artery occlusion, male Sprague Dawley rats (n = 31) were randomly assigned to receive the ARNI LCZ696, the ARB valsartan, or corn oil only (MR control). Excised mitral leaflets and left ventricle (LV) were analyzed, and valvular endothelial cells were evaluated focusing on molecular changes. LCZ696 significantly attenuated LV dilatation after 6 weeks when compared with the control group (LV end-diastolic volume, 461.3 \u00b1 13.8 \u00b5L versus 525.1 \u00b1 23.6 \u00b5L; p &lt; 0.05), while valsartan did not (471.2 \u00b1 8.9 \u00b5L; p &gt; 0.05 to control). Histopathological analysis of mitral leaflets showed that LCZ696 strongly reduced fibrotic thickness compared to the control group (28.2 \u00b1 2.7 \u00b5m vs. 48.8 \u00b1 7.5 \u00b5m; p &lt; 0.05). Transforming growth factor-\u03b2 and downstream phosphorylated extracellular-signal regulated kinase were also significantly lower in the LCZ696 group. Consequently, excessive endothelial-to-mesenchymal transition (EndoMT) was mitigated in the LCZ696 group compared to the control group and leaflet area was higher (11%) in the LCZ696 group than in the valsartan group. Finally, the MR extent was significantly lower in the LCZ696 group and functional improvement was observed. In conclusion, neprilysin inhibitor has positive effects on LV reverse remodeling and also attenuates fibrosis in MV leaflets and restores adaptive growth by directly modulating EndoMT.<\/jats:p>","DOI":"10.3390\/ijms22168598","type":"journal-article","created":{"date-parts":[[2021,8,10]],"date-time":"2021-08-10T08:57:14Z","timestamp":1628585834000},"page":"8598","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Effect of Neprilysin Inhibition for Ischemic Mitral Regurgitation after Myocardial Injury"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2250-7948","authenticated-orcid":false,"given":"Sahmin","family":"Lee","sequence":"first","affiliation":[{"name":"Division of Cardiology, Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea"},{"name":"Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyo-Sook","family":"Hwang","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2278-7698","authenticated-orcid":false,"given":"Naaleum","family":"Song","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea"},{"name":"Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geun-Hyung","family":"Kang","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyoung-Hee","family":"Choi","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eunhye","family":"Ji","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong-Min","family":"Song","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duk-Hyun","family":"Kang","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2996","DOI":"10.1093\/eurheartj\/ehq411","article-title":"Ischaemic mitral regurgitation: Pathophysiology, outcomes and the conundrum of treatment","volume":"31","author":"Pierard","year":"2010","journal-title":"Eur. 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