{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T15:13:12Z","timestamp":1780499592805,"version":"3.54.1"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,4,25]],"date-time":"2024-04-25T00:00:00Z","timestamp":1714003200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>Diastolic dysfunction was induced in male C57\/BL6J mice (<jats:italic>n<\/jats:italic>\u2009=\u200920) by combining high-fat diet, L-NG-nitroarginine methyl ester, and angiotensin II administration, and was compared to sham controls (<jats:italic>n<\/jats:italic>\u2009=\u200918). Mice were randomized to subcutaneous miR-181c-5p antagomiR (INH) or scrambled antagomiR injections (40\u2005mg\/kg\/week). HF mice demonstrated diastolic dysfunction and increased fibrosis, which was attenuated by INH treatment. Remarkably, HF\u2009+\u2009INH 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 <jats:italic>Tgfbr1<\/jats:italic> in HF\u2009+\u2009INH mice, while INH treatment reduced renal but not cardiac <jats:italic>Vegfa<\/jats:italic> expression in all mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study demonstrates cardiac anti-fibrotic effects of miR-181c-5p inhibition in a rodent HF model through targeting of <jats:italic>Tgfbr1<\/jats:italic> in the heart. Despite improved diastolic function, HF\u2009+\u2009INH mice had higher mortality due to increased predisposition for TMA, increased renal fibrosis and glomerular damage, associated with <jats:italic>Vegfa<\/jats:italic> downregulation in kidneys.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcvm.2024.1383046","type":"journal-article","created":{"date-parts":[[2024,4,25]],"date-time":"2024-04-25T04:44:28Z","timestamp":1714020268000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Divergent cardiac and renal effects of miR-181c-5p inhibition in a rodent heart failure\u00a0model"],"prefix":"10.3389","volume":"11","author":[{"given":"Jente R. 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