Abstract Or104: The Evaluation of Anti-Fibrotic and Anti-Thrombotic Effects of an Oral Galectin-3 Inhibitor in a Mouse Model of Venous Thrombosis

Objective: Post-thrombotic syndrome (PTS) is a debilitating complication of deep vein thrombosis (DVT), and anticoagulation therapies for DVT often fail to prevent PTS. Experimental PTS may in part be mediated by matrix metalloproteinase (MMP)activity. Galectin-3 (Gal-3), encoded by the LGALS3 gene, plays a pivotal role in cell migration, activation, and inflammation. Previous studies in models of liver fibrosis and atherosclerosis have suggested that Gal-3 inhibition can modulate fibrotic and inflammatory responses. We hypothesized that Gal-3 inhibition could reduce vein wall fibrosis in a rodent model of venous thrombosis (VT). Methods: Using a mouse model of complete inferior vena cava (IVC) stasis, C57BL/6 WT mice were treated with an oral Gal-3 inhibitor (GB1107, 10 mg/kg) for 8 days following induction of venous thrombosis. Masson’s trichrome staining of thrombosed IVC sections were evaluated to quantify vein wall collagen deposition. In vitro , inflammatory markers of fibrosis were assessed by qRT-PCR. THP-1 immortalized human macrophages (Mo/Mphage) were stimulated with vehicle control versus Gal-3 inhibitor. An endothelial-leukocyte adhesion functional assay was used to evaluate the effects of Gal-3 inhibition. Statistical analysis was performed using GraphPad Prism software. Results: In vivo , Masson’s trichrome staining revealed that Gal-3 inhibition reduced vein wall collagen deposition compared to untreated controls 8 days post-VT (*p<0.05, Figure 1) In vitro , Gal-3 inhibition significantly decreased Matrix Metalloproteinase-9 ( mmp-9 ) expression in THP-1 Mo/Mphage cells compared to untreated controls (**p<0.01, Figure 1). Finally, in a functional endothelial-leukocyte adhesion assay, Gal-3 inhibition significantly decreased cell adhesion compared to stimulated with TNF-α (****p<0.0001, Figure 1). Conclusions: Galectin-3 inhibition significantly reduced vein wall fibrosis in vivo . Potential antifibrotic mechanisms of gal-3 indicated by our in vitro data include disruption of immune cell- endothelial cell interactions and suppression of monocyte derived mmp9 gene expression. Keywords: Galectin-3, venous thrombosis, post-thrombotic syndrome, fibrosis, inflammation, mouse model.