AUTHOR=Boen Jente R. A. , Gevaert Andreas B. , Dendooven Amélie , Krüger Dustin , Tubeeckx Michiel , Van Fraeyenhove Jens , Bruyns Tine , Segers Vincent F. M. , Van Craenenbroeck Emeline M. 

TITLE=Divergent cardiac and renal effects of miR-181c-5p inhibition in a rodent heart failure model

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=Volume 11 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2024.1383046

DOI=10.3389/fcvm.2024.1383046

ISSN=2297-055X

ABSTRACT=MiR-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 RESULTS: Diastolic 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 (40mg/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.CONCLUSION: This 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.