Mineralocorticoid receptor antagonists modulate ST2 signaling pathway in chronic heart failure

Purpose: IL-33 is an IL-1-like cytokine that signals via the cardiac transmembrane receptor ST2L. IL-33/ST2L signaling is a novel cardioprotective fibroblast-cardiomyocyte paracrine system that in response to biomechanical strain reduces cardiac fibrosis and hypertrophy. The soluble ST2 isoform (sST2) is a decoy receptor that attenuates the cardioprotective effects associated to IL-33/ST2L signaling and serum sST2 levels predicted outcome in patients with acute myocardial infarction (MI) and heart failure (HF). The present study aimed to analyze whether the IL-33/ST2L signaling is involved in the anti-fibrotic effect of mineralocorticoid receptor antagonists (MRAs), which prevent cardiac remodeling and slow HF. Methods: Male Wistar rats (6-8 weeks old, 200-270 g) were used and MI was induced by permanent ligation of the left anterior descending coronary. Animals were randomly assigned to not receive treatment (MI group, n=12) or to receive a MRA from the day of surgery and for 4 weeks, either eplerenone (Eple, n=18) or spironolactone (Spiro, n=18) at the dose of 100 mg/kg/day. A sham group was used as control (n=8). The mRNA expression levels of ST2L, sST2, IL-33, collagen I and collagen III in the infarcted area of the left ventricle were analyzed by quantitative RT-PCR. Each value is expressed as fold of control. Results: Compared to sham group, MI group showed higher levels of ST2L, sST2 and IL-33 in the infarcted area (35.8, 18.4 and 173.6, p<.001, respectively). ST2L and sST2 expression levels were reduced by the treatment with Eple (8.6, p=.004 and 7.6, p=.011, respectively). Spiro reduced ST2L (14.9, p=.034) but not sST2 (14.1, p=0.064). Interestingly, neither Eple nor Spiro were able to reduce the high expression level of the protective cytokine IL-33 reached in MI rats. In the infarcted area, MI group showed higher levels of fibrosis markers collagen I and collagen III compared with the sham group (61.2, p<.001 and 169.9, p=.038, respectively). The treatment with either Eple or Spiro significantly reduced collagen I (12.9, p=.016 or 8.5, p=.008, respectively) and collagen III expression (6.4, p=.003 or 2.8, p=.019, respectively). In addition, the expression levels of ST2L, sST2 and IL-33 were correlated with each other (p<.001) while ST2L and sST2, but not IL-33, were correlated with collagen I and collagen III (p<.0001). Conclusions: Our results suggest for the first time that the IL-33/ST2L signaling may be an important mechanism involved in the antifibrotic effect of MRAs in the context of postinfarction HF.