Galectin-3 signaling pathway is modulated by mineralocorticoid receptor antagonists in chronic heart failure

Purpose: Galectin-3 (Gal-3) plays an active role in the development of cardiac fibrosis, inflammation and remodeling in heart failure (HF). Higher concentration of Gal-3 is associated with worse prognosis, increased risk for incident HF and mortality. Although the anti-inflammatory and anti-fibrotic properties of mineralocorticoid receptor antagonists (MRAs) are documented in heart failure context, the involved mechanisms have not been well elucidated. Thi study aimed to analyze whether MRAs modulate the Gal-3 signaling in an experimental model of HF and their association with cardiac remodeling. Methods: Myocardial infarction (MI) was induced by ligation of the left anterior descending coronary in 56 male Wistar rats (200-270 g). 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 modulation of Gal-3 expression and the involvement of TGF-β/Smad3 signaling pathway were evaluated by quantitative RT-PCR in the infarcted area of the left ventricle. Markers of cardiac fibrosis (collagen I, collagen III, TIMP1) and inflammation (IL-6, TNFα) were also analyzed by RT-PCR. Each value is expressed as fold of control. Results: Compared to sham group, Gal-3 expression was induced in the infarcted area of MI rats (53.7, p<.001). The expression levels of TGF-β and Smad3, molecules involved in Gal-3 signaling, were also higher in the MI group (7.8, p<.001 and 6.7, p=.012, respectively) and correlated with Gal-3 (p<0.001 for both). In addition, Gal-3 correlated with markers of fibrosis as collagen I (p<0.001), collagen III (p=0.41) and TIMP1 (p<0.001); and markers of inflammation as IL-6 (p<0.001) and TNFα (p<0.001). Gal-3 expression was reduced by the treatment with either Eple (10.9, p=.04) or Spiro (12.4, p=.047); but only Eple was able to reduce TGF-β (2.9, p=.012) and Smad3 (1.1, p=.017). The treatment with either Eple or Spiro significantly reduced the expression level of collagen I (12.9, p=.016 and 8.5, p=.008; respectively), collagen III (6.4, p=.003 and 2.8, p=.019) and TIMP1 (17.5, p=.003 and 22.5, p=.02). Eple, but no Spiro, reduced expression level of TNFα (2.5, p=.01), whereas IL-6 was not affected. Conclusions: This study shows for the first time the modulating role of MRAs on Gal-3 cardiac expression and suggests that the inhibition of Gal-3 expression may be an important mechanism involved in the anti-fibrotic effect of MRAs in the context of postinfarction HF.