The Aldosterone Receptor Antagonist Eplerenone Inhibits Isoproterenol-Induced Collagen-I and 11β-HSD1 Expression in Rat Cardiac Fibroblasts and the Left Ventricle

• Published in: Biological & pharmaceutical bulletin 2017/10/01, Vol.40(10), pp.1716-1723
• Main Authors: Hori, Yasutomo, Touei, Daisuke, Saitoh, Ryuta, Yamagishi, Maki, Kanai, Kazutaka, Hoshi, Fumio, Itoh, Naoyuki
• Format: Article
• Language: English
• Subjects: 11-beta-Hydroxysteroid Dehydrogenase Type 1 - genetics; 11-beta-Hydroxysteroid Dehydrogenase Type 1 - metabolism; 11β-Hydroxysteroid dehydrogenase; Adrenergic beta-Agonists - pharmacology; Adrenergic receptors; Aldosterone; Animals; beta-adrenoceptor; cardiac fibrosis; Cells, Cultured; Collagen; Collagen Type I - genetics; Collagen Type I - metabolism; eplerenone; Extracellular signal-regulated kinase; fibroblast; Fibroblasts; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibrosis; Heart; Heart diseases; Heart Ventricles - drug effects; Heart Ventricles - metabolism; Heart Ventricles - pathology; Isoproterenol; Isoproterenol - pharmacology; Kinases; Male; MAP kinase; Mineralocorticoid Receptor Antagonists - pharmacology; mRNA; Phosphorylation; Protein kinase; Rats; Rats, Inbred WKY; Rodents; Spironolactone - analogs & derivatives; Spironolactone - pharmacology; Ventricle
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b17-00291

β-Adrenergic receptor (β-AR)-induction of collagen-I synthesis is partially mediated by the cardiac mineralocorticoid receptor (MR) system. However, it remains unclear whether the selective MR antagonist, eplerenone, inhibits collagen-I synthesis induced by β-AR stimulation. We investigated the effects of eplerenone on the responses to a non-selective β-AR agonist, isoproterenol, which induced collagen-I synthesis in primary cardiac fibroblasts (CFs) and the left ventricle. mRNAs encoding the MR and 11β-hydroxysteroid dehydrogenase type I (11β-HSD1) were evident in the left ventricle and primary CFs. mRNAs encoding the CYP family 11 subfamily B member 2 (CYP11-B2) were not detected, even after isoproterenol treatment. In vivo, isoproterenol induced collagenous fiber accumulation in the left ventricle. The phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), 11β-HSD1 levels, and mRNA/protein levels of collagen-I increased upon exposure to isoproterenol, but these increases were inhibited by eplerenone co-treatment. In primary CFs, isoproterenol increased the phosphorylation of ERK1/2 and the expression levels of both 11β-HSD1 and collagen-I; these isoproterenol-attributable effects were inhibited by co-treatment with eplerenone and PD98059, a specific inhibitor of mitogen-activated protein kinase/ERK kinase activity. The results suggest that 11β-HSD1 but not CYP11-B2 is expressed in primary CFs. Eplerenone inhibited isoproterenol-induced ERK1/2 phosphorylation and expression of 11β-HSD1 and collagen-I in primary CFs, as well as the progression of cardiac fibrosis in the left ventricle. Therefore, eplerenone inhibited the isoproterenol-induced increases in 11β-HSD1 and collagen-I expression in primary CFs, and progression of cardiac fibrosis in the left ventricle.