Galectin-3 Activation and Inhibition in Heart Failure and Cardiovascular Disease: An Update

Abstract

Galectin-3 is a versatile protein orchestrating several physiological and pathophysiological processes in the human body. In the last decade, considerable interest in galectin-3 has emerged because of its potential role as a biotarget. Galectin-3 is differentially expressed depending on the tissue type, however its expression can be induced under conditions of tissue injury or stress. Galectin-3 overexpression and secretion is associated with several diseases and is extensively studied in the context of fibrosis, heart failure, atherosclerosis and diabetes mellitus. Monomeric (extracellular) galectin-3 usually undergoes further "activation" which significantly broadens the spectrum of biological activity mainly by modifying its carbohydrate-binding properties. Self-interactions of this protein appear to play a crucial role in regulating the extracellular activities of this protein, however there is limited and controversial data on the mechanisms involved. We therefore summarize (recent) literature in this area and describe galectin-3 from a binding perspective providing novel insights into mechanisms by which galectin-3 is known to be "activated" and how such activation may be regulated in pathophysiological scenarios.

Keywords: Galectin-3; carbohydrate binding domain; cardiovascular disease; cell-cell adhesion; extracellular matrix; fibrosis; heart failure; interaction; renal disease.

Figure 1

Galectin-3 was previously known by several names including Mac-2 antigen, IgE-binding protein, carbohydrate-binding protein and L-29. Although the historical nomenclature is obsolete, it highlights the various fields in which galectin-3 research has evolved.

Figure 2

Western blot analysis of different tissues, adapted from Kim et al . This figure illustrates the variability of galectin-3 in different murine tissues with the highest expression in lung, spleen, stomach, colon, uterus and ovary. While liver, kidney and adrenal gland display a moderate galectin-3 expression, baseline expression in the heart, pancreas and ileum is very low.

Figure 3

The role of galectin-3 in inflammation is ambiguous. Some studies suggest that apoptosis of neutrophils and their clearance by macrophages is reduced in galectin-3 KO mouse models. However, further research needs to be conducted as increased intracellular galectin-3 levels are usually associated with cellular longevity. The role of galectin-3 in fibrosis is well-established, and increased galectin-3 levels contribute to (myo)fibroblast activation through a TGF-β independent pathway and also through a TGF-β dependent pathway. Syndecans also play an important role, especially by affecting profibrotic signalling in cardiac fibroblasts, and possibly also by interacting with galectin-3. Furthermore, galectin-3 can also affect the fibrotic pathway by inducing alternative (M2) activation in macrophages. KO: knockout; TGF-β: transforming growth factor β

Figure 4

A simplified depiction of galectin-3 structure indicating the carbohydrate recognition domain (CRD), H-domain and the amino-terminal (N-terminal). The CRD is globular and consists of several carbohydrate binding-grooves. The most frequently described carbohydrate-binding sites are the canonical S-face and the non-canonical F-face. S-face binds β-galactosides such as lactose, while larger carbohydrates such as MCPs and GMs are reported to bind to the F-face. The CRD continues as a long and slender tail which ends in the N-terminal; the N-terminal does not exhibit carbohydrate-binding activity. CRD: carbohydrate recognition domain; N-terminal: amino terminal; MCP: modified citrus pectin; GM: galactomannan

FIGURE 5

In this illustration, we depict the role of self-interactions in galectin-3 bioactivation. Intramolecular interactions between the carbohydrate recognition domain (CRD) and the N-terminal render the galectin-3 molecule relatively inert in the closed conformer state; the galectin-3 molecule can still bind S-face ligands such as lactose in this state. Release of the N-terminal from the F-face results in the open conformer which is biologically more active. The open conformer can bind to various ligands (both S-face ligands and F-face ligands) and can also undergo dimerization or oligomerization. Two types of intermolecular interactions, N-terminal interactions and CRD-CRD interactions, are usually observed during multimerization and this results in increased biological activity of galectin-3. CRD: carbohydrate recognition domain

FIGURE 6

Galectin-3 lattices are focal, three-dimensional frameworks consisting of galectin-3 in its different forms and multimerization states, and is envisioned to be an additional layer of membrane organization. Galectin-3 interacts with various binding partners, usually carbohydrate molecules that project from glycoproteins and glycolipids, regulating several important biological processes. Galectin-3 lattices are a part of the larger “lectin-saccharide” lattices.