BioProject

The overall objective of the study was to screen for microRNAs regulated by aldosterone and salt in rat left ventricles . More...

The overall objective of the study was to screen for microRNAs regulated by aldosterone and salt in rat left ventricles . Primary aldosteronism is characterized by excess aldosterone (ALDO) secretion independent of the renin-angiotensin system and accounts for ~10% of hypertensive patients. Excess ALDO, inappropriate for the salt intake status, causes cardiac hypertrophy, inflammation, fibrosis and hypertension. The molecular mechanisms that trigger the onset and progression of ALDO-mediated cardiac injury are poorly understood. MicroRNAs (miRNAs) are endogenous, small, non-coding RNAs that have been implicated in diverse cardiac pathologies, yet very little is known about their regulation and role in ALDO-mediated cardiac injury. To elucidate the regulation of miRNAs in ALDO-mediated cardiac injury, we performed a time-series analysis of left ventricle (LV) miRNA expression. Uninephrectomized male Sprague Dawley rats were treated with ALDO (0.75 µg/h) infusion and SALT (1.0% NaCl/0.3% KCl) in the drinking water for up to 8 weeks. ALDO/SALT time-dependently modulated the expression of multiple miRNAs in the LV. miR-21 was the most upregulated miRNA after 2 weeks of treatment and remained elevated until the end of the study. To elucidate the role of miR-21 in ALDO/SALT-mediated cardiac injury, miR-21 was downregulated using antagomirs in ALDO/SALT-treated rats. miR-21 downregulation exacerbated ALDO/SALT-mediated cardiac hypertrophy, fibrosis and inflammation markers gene expression, interstitial and perivascular fibrosis, OH-proline content and cardiac dysfunction. These results suggest that ALDO/SALT-mediated cardiac miR-21 upregulation may be a compensatory mechanism that mitigates ALDO/SALT-mediated cardiac deleterious effects. We speculate that miR-21 supplementation would have beneficial effects in reverting or mitigating cardiac injury and dysfunction in patients with primary aldosteronism. Overall design: Eight-week old male Sprague Dawley rats (Harlan Laboratories) were uninephrectomized and the next day randomly assigned to Control or Aldosterone/Salt (ALDO/SALT) experimental groups. ALDO (0.75 µg/h, Steraloids) was administered in PEG 300 (vehicle, Fluka) by subcutaneously implanted osmotic minipumps (Alzet 2004, Durect). SALT (1.0 % NaCl) was administered in the drinking fluid instead of tap water. ALDO-treated animals were supplemented with 0.3 % KCl in the drinking fluid to avoid hypokalemia. Animals were treated for 2, 7, 14, 28 or 56 days. Three animals per group (treatment, time) were processed individually as biological replicates. At the indicated time points, the left ventricle was excised, total RNA extracted and processed for microRNAs microarrays. Less...