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Aldosterone Induces Cardiotrophin-1 Expression in HL-1 Adult Cardiomyocytes

Division of Cardiovascular Sciences (N.L.-A., C.I., I.G., J.D., M.A.F.), Centre for Applied Medical Research, and Department of Cardiology and Cardiovascular Surgery (J.D.), University Clinic, University of Navarra, 31008 Pamplona, Spain

Address all correspondence and requests for reprints to: María Antonia Fortuño, Ph.D., Centre for Applied Medical Research., Universidad de Navarra, Avenida Pio XII, 55, 31008 Pamplona, Spain. E-mail: fortuto{at}unav.es.

Aldosterone (ALDO) may induce cardiac hypertrophy by nonhemodynamic mechanisms that are not completely defined. Cardiotrophin-1 (CT-1) is a cytokine that exerts hypertrophic actions on isolated cardiomyocytes and promotes cardiac hypertrophy in vivo. We investigated whether ALDO induces CT-1 expression in HL-1 cardiomyocytes aiming at the possibility that the cytokine is involved in ALDO-induced cardiomyocyte hypertrophy. mRNA and protein expression were quantified by RT-PCR and Western blot. Cardiomyocyte area, as an index of hypertrophy, was assayed by image analysis in phalloidin-stained HL-1 cells. ALDO addition to adult HL-1 cardiomyocytes increased (P < 0.01) CT-1 mRNA and protein expression in a concentration-dependent manner. This effect was abrogated by actinomycin D, the mineralocorticoid and glucocorticoid receptor antagonists spironolactone and RU486, respectively, and the p38 MAPK blocker SB203580. CT-1 signaling pathway blockade with specific antibodies against the cytokine and its two receptor subunits avoided (P < 0.01) -sarcomeric actin and c-fos protein overexpression as well as cell size increase induced by ALDO in HL-1 cells. In vivo, a single ALDO injection acutely increased (P < 0.01) the myocardial expression of CT-1 in C57BJ6 wild-type mice but not CT-1-null mice. The bolus of the mineralocorticoid increased (P < 0.01) ANP and c-fos mRNA expression in the myocardium of wild-type mice, whereas no changes were observed in CT-1-null mice. In summary, ALDO induces CT-1 expression in adult HL-1 cardiomyocytes via genomic and nongenomic mechanisms. CT-1 up-regulation could have relevance in the direct hypertrophic effects of ALDO in cardiomyocytes.