Cross-talk between mineralocorticoid receptor/angiotensin II type 1 receptor and mitogen-activated protein kinase pathways underlies aldosterone-induced atrial fibrotic responses in HL-1 cardiomyocytes

Background: Aldosterone is increasingly recognized for its involvement in atrial structural remodeling. However, the precise molecular mechanisms and signal pathways underlying aldosterone-induced atrial fibrosis are unknown. Methods: Western blotting was used to investigate the effects of aldosterone on the expression of mineralocorticoid receptor (MR), angiotensin II type I receptor (AT1), mitogen-activated protein kinases (MAPKs), and fibrotic marker proteins in cultured HL-1 cardiomyocytes. Results: Aldosterone upregulated MR and AT1 expressions in a concentration-dependent and time-dependent manner. Aldosterone (10(-6) M) significantly and time-dependently increased activation of the extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), p38MAPK pathways, and the protein expression of collagen 1A and 3A (COL1A and COL3A), transforming growth factor (TGF)-beta 1, and alpha-smooth muscle actin (SMA). Pre-treatment with eplerenone (10(-10) M) prevented the increased expression of MR, MAPK signals and the above profibrotic molecules, but amplified the increase in AT1 level stimulated by aldosterone (10-6 M). Pre-treatment with losartan (10(-10) M) or MAPK pathway inhibitors (U0126 or SP600125) abolished aldosterone-induced MR upregulation and significantly inhibited the expression of the above fibrotic marker proteins, indicating the critical role of MR and the requirement for active AT1 in the development of aldosterone-induced atrial fibrosis. Conclusions: Elevated MR activity plays a central role in aldosterone-mediated activation of the MAPK signaling pathway and subsequent profibrotic effects in HL-1 atrial cells. MR/AT1 and the MAPK signaling pathway interact to trigger the molecular mechanism underlying the aldosterone-induced atrial fibrotic response. Our results support the view that MR blockade in conjunction with AT1 blockade can prevent the occurrence of atrial fibrillation. (C) 2013 Published by Elsevier Ireland Ltd.