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- Title
Effect of Neprilysin Inhibition for Ischemic Mitral Regurgitation after Myocardial Injury.
- Authors
Lee, Sahmin; Hwang, Hyo-Sook; Song, Naaleum; Kang, Geun-Hyung; Choi, Kyoung-Hee; Ji, Eunhye; Song, Jong-Min; Kang, Duk-Hyun
- Abstract
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 ± 13.8 µL versus 525.1 ± 23.6 µL; p < 0.05), while valsartan did not (471.2 ± 8.9 µL; p > 0.05 to control). Histopathological analysis of mitral leaflets showed that LCZ696 strongly reduced fibrotic thickness compared to the control group (28.2 ± 2.7 µm vs. 48.8 ± 7.5 µm; p < 0.05). Transforming growth factor-β 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.
- Subjects
MYOCARDIAL injury; MITRAL valve insufficiency; NEPRILYSIN; CORONARY occlusion; ANGIOTENSIN receptors; TRANSFORMING growth factors-beta
- Publication
International Journal of Molecular Sciences, 2021, Vol 22, Issue 16, p8598
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms22168598