Galectin-3 deficiency ameliorates fibrosis and remodeling in dilated cardiomyopathy mice with enhanced mst1 signaling

My Nhan Nguyen, Mark Ziemann, Helen Kiriazis, Yidan Su, Zara Thomas, Qun Lu, Daniel G. Donner, Wei Bo Zhao, Haloom Rafehi, Junichi Sadoshima, Julie R. McMullen, Assam El-Osta, Xiao Jun Du

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10 Scopus citations

Abstract

Dilated cardio-myopathy (DCM) is a major cause of heart failure without effective therapy. Fibrogenesis plays a key role in the development of DCM, but little is known of the expression of the profibrotic factor galectin-3 (Gal-3) and its role in DCM pathophysiology. In a mouse DCM model with 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 crossbreeding Mst1-TG mice with Gal-3 KO mice. The DCM phenotype was assessed by echocardiography and micromanometry. Cardiac expression of Gal-3 and fibrosis were determined. The cardiac transcriptome was profiled by RNA sequencing. Mst1-TG mice at 38 mo of age exhibited upregulated expression of Gal-3 by ~40-fold. TG mice had dilatation of cardiac chambers, suppressed left ventricular (LV) ejection fraction, poor LV contractility and relaxation, a threefold increase in LV collagen content, and upregulated fibrotic genes. Four-month treatment with MCP showed no beneficial effects. Gal-3 deletion in Mst1-TG mice attenuated chamber dilatation, organ congestion, and fibrogenesis. RNA sequencing identified profound disturbances by Mst1 overexpression in the 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. We conclude that cardiac Mst1 activation leads to marked Gal-3 upregulation and transcriptome disturbances in the heart. Gal-3 deficiency attenuated cardiac remodeling and fibrotic signaling. NEW & NOTEWORTHY We found in a transgenic mouse dilated cardiomyopathy (DCM) model a pronounced upregulation of galectin-3 in cardiomyocytes. Galectin-3 gene deletion reduced cardiac fibrosis and fibrotic gene profiles and ameliorated cardiac remodeling and dysfunction. These benefits of galectin-3 deletion were in contrast to the lack of effect of treatment with the galectin-3 inhibitor modified citrus pectin. Our study suggests that suppression of galectin-3 mRNA expression could be used to treat DCM with high cardiac galectin-3 content.

Original languageEnglish (US)
Pages (from-to)H45-H60
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume316
Issue number1
DOIs
StatePublished - Jan 2019

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All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Keywords

  • Dilated cardiomyopathy
  • Fibrosis
  • Galectin-3
  • Heart failure
  • Mammalian sterile 20-like kinase 1
  • Remodeling

Cite this

Nguyen, M. N., Ziemann, M., Kiriazis, H., Su, Y., Thomas, Z., Lu, Q., Donner, D. G., Zhao, W. B., Rafehi, H., Sadoshima, J., McMullen, J. R., El-Osta, A., & Du, X. J. (2019). Galectin-3 deficiency ameliorates fibrosis and remodeling in dilated cardiomyopathy mice with enhanced mst1 signaling. American Journal of Physiology - Heart and Circulatory Physiology, 316(1), H45-H60. https://doi.org/10.1152/ajpheart.00609.2018