Genetic Inhibition of Galectin-3 Suppressed Cardiac Fibrosis and Improved Function in a Mouse Model of Dilated Cardiomyopathy

Abstract

Background: Pre-clinical studies have consistently reported a 2∼5 fold increase in expression of Galectin-3 (Gal-3) in different heart disease models, and beneficial effects of anti-Gal-3 inhibitors. It remains unknown whether Gal-3 expression levels differ in dilated cardiomyopathy (DCM), and the effects of anti-Gal-3 interventions. We determined Gal-3 expression in transgenic (TG) mice with cardiac-restricted overexpression of mammalian sterile 20-like kinase 1 (Mst1), and studied the effects of Gal-3 gene deletion. Methods: Gal-3 deletion in Mst1-TG mice was achieved by cross-breeding Mst1-TG mice with Gal-3 knockout (KO) mice to produce TG, TG/Gal-3 KO and non-TG (NTG) genotypes. Male mice were studied (n = 6-12/group). Echocardiography (Vevo2100 system), gene expression (RT-PCR), Gal-3 protein levels (ELISA), and collagen content (hydroxyproline assay) were all measured. Results: Relative to NTG controls, TG mice had atrial dilatation (by 3-fold), suppressed left ventricular (LV) ejection fraction (EF, 27 ± 2 vs 55 ± 4%), higher myocardial collagen content (by 3-fold), and upregulated fibrotic genes (4-8 fold). Gal-3 expression was increased in TG hearts by 35-40-fold at mRNA and protein levels compared with NTG. Gal-3 gene deletion in TG mice was associated with lower cardiac fibrosis (by 17%) and suppressed expression of fibrotic genes (by 40-70%). Echocardiography revealed reduced LV volume at end-diastole (51 ± 2 vs 70 ± 7 μL) and improved EF (37 ± 2 vs 27 ± 2%, all p < 0.01). Conclusion: Gal-3 expression is markedly increased in Mst1-TG hearts exhibiting DCM. Gal-3 gene deletion effectively suppressed cardiac fibrotic signalling and LV dilatation, and improved function. Thus, suppression of Gal-3 expression may form a new therapeutic approach in DCM.