Galectin-3 deficiency ameliorates fibrosis and remodelling in dilated cardiomyopathy mice with enhanced Mst1 signaling.
Am J Physiol Heart Circ Physiol. 2018 Nov 02;:
Authors: Nguyen MN, Ziemann M, Kiriazis H, Su Y, Donner DG, Zhao WB, Lu Q, Rafehi H, Sadoshima J, McMullen JR, El-Osta A, Du XJ
Dilated cardiomyopathy (DCM) is a major cause of heart failure without effective therapy. Fibrogenesis plays a key role in DCM development but little is known on the expression of a pro-fibrotic factor galectin-3 (Gal-3) and its role in DCM pathophysiology. In a mouse DCM model by transgenic (TG) overexpression of mammalian sterile 20-like kinase 1 (Mst1), we studied Gal-3 expression and effects of the Gal-3 inhibitor modified citrus pectin (MCP) or Gal-3 gene knockout (KO). Gal-3 deletion in TG mice (TG/KO) was achieved by cross-breeding Mst1-TG with Gal-3 KO mice. DCM phenotype was assessed by echocardiography and micromanometry. Cardiac expression of Gal-3 and fibrosis were determined. Cardiac transcriptome was profiled by RNA sequencing. Mst1-TG mice of 3-8 months of age exhibited upregulated expression of Gal-3 by approximately 40-fold. TG mice had dilatation of cardiac chambers, suppressed left ventricular (LV) ejection fraction, poor LV contractility and relaxation, 3-fold increase in LV collagen content and upregulated fibrotic genes. Four-month treatment with MCP showed no beneficial effect. Gal-3 deletion in Mst1-TG mice attenuated chamber dilatation, organ congestion and fibrogenesis. RNA sequencing identified profound disturbances by Mst1 overexpression in cardiac transcriptome, which largely remained in TG/KO hearts. Gal-3 deletion in Mst1-TG mice, however, partially reversed the dysregulated transcriptional signaling involving extracellular matrix remodeling and collagen formation. In conclusion, cardiac Mst1 activation leads to marked Gal-3 upregulation and transcriptome disturbances in the heart. Gal-3 deficiency attenuated cardiac remodeling and fibrotic signaling.
PMID: 30387702 [PubMed – as supplied by publisher]