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Divergent cardiac and renal effects of miR-181c-5p inhibition in a rodent heart failure model
- Source :
- Frontiers in Cardiovascular Medicine, Vol 11 (2024)
- Publication Year :
- 2024
- Publisher :
- Frontiers Media S.A., 2024.
-
Abstract
- AimsMiR-181c-5p overexpression associates with heart failure (HF) and cardiac damage, but the underlying pathophysiology remains unclear. This study investigated the effect of miR-181c-5p inhibition on cardiac function and fibrosis in a rodent model of diastolic dysfunction, and evaluated additional effects on kidney as relevant comorbid organ.Methods and resultsDiastolic dysfunction was induced in male C57/BL6J mice (n = 20) by combining high-fat diet, L-NG-nitroarginine methyl ester, and angiotensin II administration, and was compared to sham controls (n = 18). Mice were randomized to subcutaneous miR-181c-5p antagomiR (INH) or scrambled antagomiR injections (40 mg/kg/week). HF mice demonstrated diastolic dysfunction and increased fibrosis, which was attenuated by INH treatment. Remarkably, HF + INH animals had a threefold higher mortality rate (60%) compared to HF controls (20%). Histological examination revealed increased glomerular damage in all INH treated mice, and signs of thrombotic microangiopathy (TMA) in mice who died prematurely. Quantitative polymerase chain reaction demonstrated a miR-181c-5p-related downregulation of cardiac but not renal Tgfbr1 in HF + INH mice, while INH treatment reduced renal but not cardiac Vegfa expression in all mice.ConclusionThis study demonstrates cardiac anti-fibrotic effects of miR-181c-5p inhibition in a rodent HF model through targeting of Tgfbr1 in the heart. Despite improved diastolic function, HF + INH mice had higher mortality due to increased predisposition for TMA, increased renal fibrosis and glomerular damage, associated with Vegfa downregulation in kidneys.
Details
- Language :
- English
- ISSN :
- 2297055X
- Volume :
- 11
- Database :
- Directory of Open Access Journals
- Journal :
- Frontiers in Cardiovascular Medicine
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.434e6b83d432aa3c619f3a34d5a6b
- Document Type :
- article
- Full Text :
- https://doi.org/10.3389/fcvm.2024.1383046