Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2022888 | Regulatory Peptides | 2010 | 7 Pages |
Large clinical trials have shown that mineralocorticoid receptor (MR) antagonists improve cardiovascular or total mortality in patients with heart failure or myocardial infarction even though the patients were taking angiotensin-converting enzyme inhibitors or angiotensin II receptor (AT1R) antagonists. We previously reported that cardiac fibrosis induced by aldosterone and salt (Ald–NaCl) was exaggerated in AT1aR knockout mice (AT1aR-KOs). As the association of Rho kinase and oxidative stress was reported in Ald–NaCl-induced hypertension of rats, we investigated the effects of an MR antagonist (eplerenone) and a Rho kinase inhibitor (fasudil) on Ald–NaCl-induced cardiac fibrosis in AT1aR-KOs. AT1aR-KOs were administered aldosterone (0.15 μg/h) subcutaneously using an osmotic minipump and were provided with 1% NaCl drinking water for 4 weeks. AT1aR-KOs receiving Ald–NaCl were treated with a low (30 mg/kg/day) or high (100 mg/kg/day) dose of eplerenone or a fasudil (100 mg/kg/day). Systolic blood pressure (SBP), left ventricular weight/body weight (LVW/BW), histological examination and cardiac gene expression were evaluated on day 28. Ald–NaCl treatment caused increases in SBP and LVW/BW in AT1aR-KOs, and eplerenone dose-dependently decreased SBP, LVW/BW and cardiac fibrosis. Fasudil decreased LVW/BW and cardiac fibrosis without affecting SBP. The expressions of connecting tissue growth factor (CTGF) and nicotinamide adenine dinucleotide phosphate (NADPH) components (p22phox, p47phox and p67phox) were increased in Ald–NaCl-treated AT1aR-KOs, and eplerenone or fasudil decreased the expression of CTGF and NADPH components. Phosphorylated ERM (a marker of the phosphorylation of Rho kinase) was increased in Ald–NaCl-treated AT1aR-KOs and was decreased by eplerenone. Nitrotyrosine and 4-hydroxy-2-nonenal, which indicate tissue damage via oxidative stress, were increased in AT1aR-KO and were apparently attenuated by eplerenone or fasudil. These results suggested that the Rho kinase pathway was activated to induce cardiac fibrosis by Ald–NaCl via MR in AT1aR-KOs. A Rho kinase inhibitor as well as eplerenone might be useful for cardiac damage by Ald–NaCl.