Liver sinusoidal endothelial cell (LSEC) defenestration in chronic heart failure is primarily dependent on cardiac diastolic dysfunction and is reversed by sodium-glucose cotransporter 2 inhibitor but not by angiotensin-converting enzyme inhibitor
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2026
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Abstract
AIMS: Liver sinusoidal endothelial cells (LSECs) dysfunction was demonstrated to represent an early and persistent event in chronic heart failure (CHF), preceding congestive hepatopathy and contributing to the pathophysiology of the disease. However, it remains unknown whether classical CHF pharmacotherapy would reverse LSEC defenestration. Herein, we characterised the therapeutic effects of angiotensin-converting enzyme (ACE) inhibitor - perindopril, and sodium-glucose cotransporter 2 (SGLT2) inhibitor - empagliflozin - on the cardiohepatic axis and, in particular, on LSEC defenestration in the murine model of CHF. METHODS AND RESULTS: Untreated 6-month-old Tgαq*44 mice exhibited impaired systolic and diastolic cardiac function, impaired liver perfusion, and LSEC defenestration. Perindopril (2 mg/kg, 8 weeks treatment, 4- to 6-month-old Tgαq*44) significantly improved the left (LV) and right ventricular (RV) systolic function and ameliorated liver perfusion in vivo in Tgαq*44 mice. Perindopril also displayed a pronounced hepatoprotective effect, as evidenced by proteomic analysis of isolated hepatocytes, reduced TBIL, and GGT; however, the number of LSEC fenestrations was unaffected in Tgαq*44 mice treated with perindopril. Empagliflozin (300 mg/kg, 8 weeks treatment, 4- to 6- month-old Tgαq*44) not only significantly improved the LV and RV systolic function and ameliorated liver perfusion, but also improved diastolic cardiac function and significantly reduced defenestration of LSECs. CONCLUSIONS: LSEC defenestration was primarily driven by cardiac diastolic dysfunction, not by impaired liver perfusion or hepatocyte function, and was independent of biomarkers of congestive hepatopathy in the murine model of CHF in Tgαq*44 mice. As fully reversed by SGLT2-I, but not by ACE-I, LSEC defenestration arises as a target in the treatment of the cardiohepatic axis in CHF, which is not uniformly improved by CHF pharmacotherapy.
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| Authors | Kamila Wojnar‐Lason, Marta Stojak, Grzegorz Kwiatkowski, Magdalena Giergiel, Anna Kurpińska, Urszula Tyrankiewicz, Marta Z. Pacia, Agnieszka Kij, Magdalena Sternak, Michał Pacia, Marek Grosicki, Joanna Zemła, Bartłomiej Zapotoczny, Izabela Czyżyńska-Cichoń, Stefan Chłopicki |
| Journal | cardiovascular research |
| Year | 2026 |
| DOI |
10.1093/cvr/cvag168
|
| URL | |
| Keywords | Keywords not found |
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