|Year : 2019 | Volume
| Issue : 4 | Page : 117-126
Galectin-3 and Fibrosis: Research in the Last 5 Years
Amitabha Medical Clinic and Healing Center, Santa Rosa, California, USA
|Date of Submission||21-Nov-2019|
|Date of Acceptance||20-Aug-2020|
|Date of Web Publication||31-Dec-2020|
Dr. Isaac Eliaz
Amitabha Medical Clinic and Healing Center, 398 Tesconi Ct, Santa Rosa, California
Tissue fibrosis is initially an adaptive response to organ injury, but eventually, parenchymal scarring and subsequent cellular dysfunction and organ failure ensue. Few therapies currently exist for fibrosis, especially those that target fibrogenesis. Galectin-3 (Gal-3) is a member of the lectin family of proteins, is produced predominantly by macrophages, and has essential functions in inflammation and angiogenesis. Gal-3 is activated in fibrotic models and abnormally elevated in fibrotic patients. Gal-3 inhibitors help to ameliorate or prevent fibrosis. For this review, we searched for original articles and reviews published between Jul 1, 2014, and Nov 1, 2019, using the following search terms (or combination of words) in PubMed: “galectin 3”, “fibrosis”, “heart”, “cardiac”, “liver”, “hepatic”, “lung”, “pulmonary”, “kidney”, and “renal”.
Keywords: Aldosterone, fibrosis, galectin-3, mineralocorticoid receptor antagonists
|How to cite this article:|
Eliaz I. Galectin-3 and Fibrosis: Research in the Last 5 Years. J Transl Crit Care Med 2019;1:117-26
| Introduction|| |
Overview of fibrosis
Tissue fibrosis is the result of a cascade of cellular and molecular processes that originate from disease-related injury. The fibrogenic response is adaptive initially, but over time, parenchymal scarring and subsequent cellular dysfunction and organ failure ultimately manifest. There are four major phases of the fibrogenic response. First, primary injury to the organ causes initiation of the reaction. Activation of effector cells is the second phase, and the third phase is the elaboration of the extracellular matrix. These phases overlap with the fourth phase, where deposition (and inadequate resorption) of the extracellular matrix leads to the development of fibrosis and eventually end-organ failure.
There are common pathogenic pathways involved in the fibrotic changes in different organ systems. Specific molecular pathways are identified as underlying the “wounding response.” Inflammatory cells, epithelial cells, fibrogenic effector cells, endothelial cells, and others play important roles. Various effector cells function in fibrosis, including fibroblasts, myofibroblasts, cells originating from bone marrow, and cells originating from epithelial tissues. Specific core molecular pathways are vital, such as the transforming growth factor-beta (TGF-β) pathway.
During the development of fibrosis, myofibroblasts proliferate and sense physical and biochemical stimuli using integrins and cell-surface molecules, and mediators signal for pathological tissue contraction. Organ deformation ensues, causing impairment in function. The specifics vary among organs. There are few therapies for fibrosis and fewer that specifically act on fibrogenesis. Thus, there is a need for further understanding of the pathogenesis of fibrogenesis to help discover new treatments.
Inflammation, both acute and chronic, can initiate fibrosis. Inflammation results in injury to the epithelial cells and often endothelial cells, leading to increased secretion of inflammatory mediators, such as cytokines, chemokines, and others. Various inflammatory cells are recruited, including lymphocytes, polymorphonuclear leukocytes, eosinophils, basophils, mast cells, and macrophages. These cells trigger effector cells that push forward the fibrogenic process. Macrophages may also participate in interstitial fibrosis, often along the TGF-β pathway.
Fibroblasts and myofibroblasts promote the formation of extracellular matrix proteins in fibrosis. The fibrotic scar formed by highly conserved matrix proteins consists mostly of interstitial collagens (Types I and III), cellular fibronectin, basement-membrane proteins such as laminin, and other, less abundant elements. Further, myofibroblasts are contractile; when these cells contract, they deform parenchymal structure, leading to disease pathogenesis and tissue failure.
The molecular systems underlying fibrosis are too expansive to allow for detailed discussion. Platelet-derived growth factor, connective tissue growth factor, and vasoactive peptide systems (especially angiotensin II and endothelin-1) have prominent roles. In vasoactive systems, endothelin participates in fibrosis in nearly every organ, acting through G-protein-coupled endothelin-A or endothelin-B cell-surface receptors or both. In addition, angiogenic pathways may be critical in fibrosis. Integrins, which link extracellular matrix to the cells, are also crucial in the pathogenesis of fibrosis.,
Abrogation of injury and inflammatory responses leads to resorption of extracellular matrix proteins, which promotes organ repair. However, when a chronic injury does not subside, the continuous activation of effector cells leads to repeated deposition of the extracellular matrix, progressive scarring, and organ damage. Therefore, fibrogenesis involves the give-and-take among factors promoting biosynthesis, deposition, and degradation of extracellular matrix proteins. In typical situations, matrix synthesis counterbalances with matrix-degrading metalloproteases.,, Furthermore, some antifibrogenic pathways act by removing effectors (e.g., through senescence, apoptosis, or autophagy). One example is the association of apoptosis of hepatic stellate cells with the reversal of fibrosis.
Galectin-3 (Gal-3) is a member of the lectin family of proteins, which recognizes and binds to specific carbohydrate motifs on glycosylated proteins as well as lipids. Gal-3 is produced predominantly by macrophages and has important functions in inflammation and angiogenesis.,
Gal-3 is widely expressed in the human tissues, including all types of immune cells (macrophages, monocytes, dendritic cells, eosinophils, mast cells, natural killer cells, and activated T- and B-cells), epithelial cells, endothelial cells, and sensory neurons., The Gal-3 expression is increased during embryogenesis as compared to adult life. Nonetheless, Gal-3-knockout mice can survive with few limitations, except for early senescence.
Gal-3 is mainly located in the cytoplasm and shuttles into the nucleus. It can also migrate to the cell surface and into biological fluids. The various functions of Gal-3 are largely determined by its different locations. For instance, Gal-3 promotes survival in the cytoplasm as a result of its interaction with certain survival-associated proteins, such as B-cell lymphoma-2 (BCL2) and activated guanosine-5′-triphosphate-bound K-Ras. In the nucleus, Gal-3 functions in pre-mRNA splicing and gene transcription. Extracellular Gal-3 affects cell–cell interactions, such as those between epithelial cells and the extracellular matrix. This entails that Gal-3 has an important role in cell differentiation, inflammation, fibrogenesis, and the host., Earlier research demonstrates that Gal-3 is involved in cardiovascular remodeling, in addition to several autoimmune and inflammatory processes.,,,,,,,,
A review of studies published before July 2014 demonstrated that Gal-3 is activated in the fibrotic models and is abnormally elevated in fibrotic patients. Furthermore, Gal-3 inhibitors help to ameliorate or prevent fibrosis. In the present review, we mainly focused on the literature published from July 2014 to update the role of Gal-3 in fibrotic diseases, specifically cardiac, hepatic, pulmonary, and renal.
| Methods|| |
Search strategy and selection criteria
We searched for original articles and reviews published between July 1, 2014, and November 1, 2019, using the following search terms (or combination of words) in PubMed: “Gal-3,” “fibrosis,” “heart,” “cardiac,” “liver,” “hepatic,” “lung,” “pulmonary,” “kidney,” and “renal.” We excluded articles that focused on skin healing because this was covered in a recent review and because the mechanisms of skin remodeling appear to be different, when compared to remodeling of heart, liver, lung, and kidney. The inclusion criteria consisted of only full-text articles written in English. Articles in journals with stringent peer-review processes were favored.
| Results|| |
The results are presented in [Table 1].
| Discussion|| |
Galectin-3 in fibrotic diseases
Galectin-3 in cardiac fibrosis
Protein kinase C (PKC)-α promotes cardiac fibrosis and heart failure (HF) by the stimulation of Gal-3 expression. Activation of Gal-3 expression in the atria can subsequently activate the TGF-β1/α-smooth muscle actin/collagen I (Col I) pathway in cardiac fibroblasts, which may enhance atrial fibrosis. Cardiotrophin-1 (CT-1) upregulates Gal-3, which, in turn, mediates the pro-inflammatory and pro-fibrotic myocardial effects of CT-1. An inverse association is observed between myocardial Gal-3 expression and cardiac fibrosis in patients with inflammatory cardiomyopathy, but in patients with dilated cardiomyopathy, myocardial Gal-3 expression is positively correlated with cardiac fibrosis on left ventricular (LV) biopsy. Reduction of coxsackievirus B3-induced cardiac damage and inflammatory responses, through the inhibition of Gal-3, may be achieved with the subsequent decrease of chronic fibrosis. Inhibition of Gal-3 and aldosterone (Aldo) can reverse isoproterenol-induced LV dysfunction by reducing myocardial inflammation and fibrogenesis. Modulation of Gal-3 and interleukin (IL)-33/ST2 signaling induced by mineralocorticoid receptor antagonists (MRAs) correlates with lower expression levels of fibrosis and inflammatory markers. Perindopril and PectaSol-C Modified Citrus Pectin (P-MCP, ecoNugenics, Santa Rosa, CA, USA) comparably improve ischemic HF in rabbits, by downregulating Gal-3 and reducing myocardial fibrosis. In obese animals, the Gal-3 blockade with P-MCP decreases cardiovascular fibrosis and inflammation. Gal-3 pharmacological inhibition using P-MCP improves cardiac fibrosis associated with ischemia/reperfusion (IR). P-MCP treatment prevents the increase in Gal-3, media thickness, fibrosis, and inflammation in the aorta of pressure overload (PO) rats.
Galectin-3 in hepatic fibrosis
The first-in-human, Phase 1 clinical trial in patients with histologically confirmed nonalcoholic steatohepatitis (NASH) and advanced fibrosis demonstrates that the Gal-3 pharmacological inhibitor GR-MD-02 is safe and well tolerated. dnTGF-βRII/Gal-3-/-(dn/Gal3-/-) mice were generated to confirm the critical role of Gal-3 in the pathogenesis of cholestatic liver injury, which showed impaired inflammasome activation along with significantly improved inflammation and fibrosis. P-MCP attenuated liver fibrosis through an antioxidant effect, and the inhibition of Gal-3 mediated hepatic stellate cells' activation and induction of apoptosis. Gal-3 attenuates steatosis but promotes liver injury, inflammation, and fibrosis in an obesogenic mouse model of NASH, thus demonstrating the involvement of Gal-3 in the progression of NASH. Further, the pro-fibrogenic IL-33/ST2/IL-13 pathway is Gal-3 dependent.
Galectin-3 in pulmonary fibrosis
Gal-3 contributes to the exaggerated injury and fibro-proliferative repair responses in Hermansky–Pudlak syndrome (HPS) by altering the anti-apoptotic and fibro-proliferative effects of chitinase 3-like 1 and its receptor complex in a tissue compartment-specific manner. In pulmonary adventitial fibroblasts, the necessity of Gal-3 to stimulate TGF-β1-vascular fibrosis via a STAT3 signaling cascade is proven. Gal-3-antagonists and a selective galactose-coumarin-derived Gal-3 inhibitor attenuate bleomycin-induced pulmonary fibrosis in mouse models. Elevated Gal-3 concentrations are associated with interstitial lung abnormalities coupled with a restrictive pattern, including decreased lung volumes and altered gas exchange, thus suggesting a potential role for Gal-3 in the early stages of pulmonary fibrosis. In addition, abnormal accumulation of Gal-3 may contribute to the pathogenesis of HPS pulmonary fibrosis.
Galectin-3 in renal fibrosis
Gal-3 inhibition is a viable strategy for alleviating acute kidney injury (AKI) and chronic kidney disease transition induced by cisplatin mediated by the reduction of cell apoptosis and attenuation of Col I and fibronectin. Gal-3 inhibition also suppresses PKC-α. Gal-3 inhibition attenuates early renal damage in spontaneously hypertensive rats (SHRs) as indicated by reduced albuminuria, improved renal function, and decreased renal fibrosis, epithelial–mesenchymal transition molecules, and inflammation, independently of blood pressure levels. In experimental models of mild kidney damage, the increase in renal Gal-3 expression paralleled with renal fibrosis, inflammation, and organ damage, all of which were prevented by Gal-3 blockade. In experimental hyperaldosteronism, the increase in Gal-3 expression is associated with renal fibrosis and dysfunction but is stopped by inhibition with P-MCP or genetic disruption of Gal-3. AKI induces remote cardiac dysfunction, damage, injury, and fibrosis via a Gal-3–dependent pathway, and Gal-3 originates from bone marrow-derived immune cells in this model.
Mechanisms of galectin-3 in fibrosis
Gal-3 often serves an anti-apoptotic function., It affects several different signal transduction cascades and pro-survival processes, including Ras, BCL2, and MYC., For instance, the suppression of Gal-3's anti-apoptotic function appears to be important for treating some cancer cells. Gal-3 regulates BCL2 and other BCL2 family members through direct binding., Further, lowering Gal-3 has been shown to reduce BCL2 protein levels. Gal-3 regulates a survival axis in acute myeloid leukemia (AML) cells, which may be targeted via combined inhibition with drugs such as GCS-100 and ABT-199. Gal-3 knockdown inhibits cell proliferation and invasion, induces caspase-3-dependent apoptosis, and arrests cell cycle at G1 phase. Gal-3 deficiency increases susceptibility to cisplatin-induced apoptosis, while the administration of recombinant Gal-3 attenuates cisplatin-induced AKI in Gal-3-knockout mice by preventing Bax and caspase-3-dependent apoptosis. Moreover, P-MCP attenuates cisplatin-induced AKI by suppressing PKC-α-driven apoptosis. Use of novel-specific Gal-3 inhibitor CBP. 001 in co-culture of AML cells with mesenchymal stromal cells reduced viable leukemia cell populations with induced apoptosis and augmented the chemotherapeutic effect of cytosine arabinoside (ara-C), a chemotherapeutic agent commonly used in the treatment of leukemia and lymphomas.
Cell adhesion and migration
Gal-3 can bind to many molecules that affect cell adhesion, such as integrins, cadherins, and other cell surface glycoproteins.,,,, Gal-3 can complex with integrins or other cell surface proteins (e.g., MUC-1) to propagate signaling pathways that lead to cell adhesion of tumor cells to stromal cells and promote survival signaling cascades.,,, Gal-3 can form pentamers with glycoproteins (or glycolipids), which enables it to organize molecules on the surface of the plasma membrane. This is performed along with other proteins on the extracellular surface of the plasma membrane (e.g., fibronectin and integrins) as well as proteins that reside in the intracellular side of the plasma membrane. Gal-3 binds to glycoproteins (as well as glycolipids) to form lattices that organize these proteins at the extracellular plasma membrane surface. The number of glycans contained on a glycoprotein will determine its binding to Gal-3 and therefore will affect the composition of these lattices. Kinase receptors such as TCR and CD44, integrins, and other proteins bind to Gal-3 and the composition of the lattice that is formed also depends on MGAT5-mediated effects., Regulation of Gal-3 gene expression by the integrin also offers feedback regulation of cell adhesion/motility.
Gal-3 has been reported as a pro-angiogenic molecule that is triggered during hypoxia and increases the chemotaxis and differentiation of the human umbilical vein endothelial cells by enhancing vascular endothelial growth factor (VEGF) receptor-2 signaling activation. Disruption of Gal-3 in the tumor stroma lowers macrophage-induced angiogenesis dependent on VEGF and TGF-β signaling. Further, under hypoxic conditions, Gal-3 is released by cancer cells and preferentially binds to endothelial cells – themselves induced – to increase binding by hypoxia. Upon binding to endothelial cells, Gal-3 triggers angiogenic sprouting by promoting Jagged-1/Notch signaling activation. Targeting Gal-3 by the novel, small-molecule inhibitor, 33DFTG, ameliorates pathological corneal angiogenesis as well as fibrosis. In addition, a blocker of endogenous Gal-3 significantly reduces the growth, motility, invasion, and angiogenic potential of cultured ovarian cancer (OC) cell lines and primary cells established from OC patients. Furthermore, 2- or 6-de-O-sulfated, N-acetylated heparin derivatives are Gal-3 binding inhibitors. These chemically modified heparin derivatives inhibit Gal-3-ligand binding and abolish Gal-3-mediated cancer cell-endothelial adhesion and angiogenesis. The role of Gal-3 in angiogenesis is likely tissue and context dependent.
Inflammation and oxidative stress
The fibrotic effects of Gal-3 are due to its ability to bind matrix proteins such as cell surface receptors (integrins), collagen, elastin, and fibronectin. Gal-3 transforms quiescent fibroblasts into myofibroblasts that manufacture and secrete matrix proteins, such as collagens., In addition to collagen production, Gal-3 is involved in collagen maturation, externalization, and cross-linking. Triggering of pro-inflammatory molecules is another mechanism by which Gal-3 promotes fibrosis. For instance, in human cardiac fibroblasts, Gal-3 augments the formation and the secretion of IL-1 β, IL-6, monocyte chemoattractant protein-1 (CCL-2), collagen Type I, collagen Type III, and fibronectin as well as the activity of matrix metalloproteinase (MMP)-1, MMP-2, and MMP-9.
New data suggest that Gal-3 is also involved in reactive oxygen species (ROS) generation. Gal-3 plays an important role in pulmonary arterial hypertension (PAH)-induced right ventricular remodeling through interacting with the NADPH oxidase 4 and Nox4-derived oxidative stress. Furthermore, Gal-3 decreases the peroxiredoxin-4 antioxidant system in the cardiac fibroblasts, increasing oxidative stress. Moreover, Gal-3 downregulates fumarate hydratase, thereby increasing fumarate production in human cardiac fibroblasts, which causes increased ROS levels and increased collagen production.
Aldosterone/mineralocorticoid receptor activation
Blockade of mineralocorticoid receptor (MR) stimulation (by an MRA) starkly lowers fibrosis. Mechanistic studies show that Gal-3 especially mediates cardiovascular and renal fibrosis in the pathological conditions related to high Aldo levels [Figure 1].,,,, Furthermore, hyperaldosteronism exacerbates hypertension-induced cardiovascular fibrosis by increasing Gal-3.
|Figure 1: Galectin-3 mediates the fibrotic effects of hyperaldosteronism. Aldosterone causes galectin-3 expression and release. The abrogation of these effects of aldosterone-induced fibrosis seen with genetic silencing or pharmacological inhibition of galectin-3|
Click here to view
Aldosterone/mineralocorticoid receptor regulates galectin-3 expression in vitro
In primary cultured vascular smooth muscle cells (VSMCs), Aldo was found to increase Gal-3 expression dose and time dependently via its MR. Gal-3, via its lectin activity, is a necessary mediator allowing Aldo-induced collagen Type I synthesis, because the blockade of Gal-3 with carbohydrates such as P-MCP or N-acetyl-D-lactosamine abolishes Aldo-induced collagen Type I deposition. In addition, Gal-3-depleted VSMCs do not develop fibrosis in response to Aldo, including a lack of collagen Type I deposition.
In the human cardiac fibroblasts, Aldo also increased Gal-3 expression via its MR, and Gal-3 and Aldo augment pro-inflammatory and pro-fibrotic markers, as well as metalloproteinase activities. Gal-3-silenced cells treated with Aldo did not present these effects. In support of the above, Aldo induced Gal-3 secretion in the inflammatory cells through MR and via PI3K/Akt and NF-kB transcription signaling pathways, amplifying the inflammatory response.
Galectin-3 in clinical populations
Gal-3 levels are elevated in a cohort of patients with Aldo-producing adenoma. One year after adrenalectomy, plasma Gal-3 levels decrease, corroborating the findings in mechanistic studies. However, another study found that Gal-3 levels are not increased in patients with primary hyperaldosteronism, and Gal-3 levels do not decrease after adrenalectomy. As a biomarker, increased or increasing Gal-3 may identify patients with excessive risk for poor outcomes, signifying a rapid form of HF with progressive remodeling.
In untreated congestive HF, Aldo levels are increased in proportion to the severity of the disease and are further increased by the use of diuretic treatment. Serum Gal-3 level is associated with the serum markers of cardiac extracellular matrix turnover in HF patients, suggesting that Gal-3 could be a biomarker of HF onset, morbidity, and mortality.
In morbidly obese patients presenting high Aldo levels, insulin resistance, and LV hypertrophy, high Gal-3 levels are associated with worse diastolic function. Furthermore, in patients with aortic stenosis (AS), cardiac Gal-3 is elevated and associated with markers of myocardial fibrosis and inflammation. Aldo and Gal-3 are both increased in PAH patients. Further, plasma levels of both molecules are associated with PAH severity. Gal-3 is also positively associated with Nox4 in PAH patients.
Given the connection between Aldo, Gal-3, and cardiovascular fibrosis, the predictive value of Gal-3 in patients treated with MRAs was examined. MRA treatment does not alter the prognostic value of Gal-3 in HF patients. In addition, no evidence was seen of interaction between the Gal-3 level and treatment effect of MRA. Finally, among patients with chronic HF and elevated Gal-3 concentrations, there is no benefit from the addition or intensification of MRA therapy.
| Conclusion|| |
Many studies observe increased Gal-3 levels in patients with fibrosis affecting different tissues.,, Studies that examined the pathogenic role of Gal-3 in fibrosis identified Gal-3 as the link between macrophages, fibroblasts, and pro-fibrotic phenotype. These observations have led to the concept of a Gal-3/macrophage/fibroblast “axis” [Figure 2]. Many results suggest that Gal-3 is a useful new simple biomarker in the prediction of disease related to the heart, liver, lung, or kidney and mortality associated with these diseases. Its inhibition represents a promising therapeutic strategy against tissue fibrosis.
|Figure 2: The galectin-3/macrophage/fibroblast axis. Galectin-3 promotes fibrosis through multiple mechanisms. It activates fibroblasts directly, and also via syndecans and TGF-β. It also induces alternative activation in macrophages. Finally, galectin-3 reduces apoptosis of neutrophils, thereby leading to increased inflammation and subsequent fibrosis. TGFβ: Transforming growth factor-beta; TGFβR: Transforming growth factor-beta receptor|
Click here to view
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Rockey DC, Bell PD, Hill JA. Fibrosis-A common pathway to organ injury and failure. N Engl J Med 2015;372:1138-49.
Wynn TA. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol 2004;4:583-94.
Meng XM, Nikolic-Paterson DJ, Lan HY. Inflammatory processes in renal fibrosis. Nat Rev Nephrol 2014;10:493-503.
Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G. The myofibroblast: One function, multiple origins. Am J Pathol 2007;170:1807-16.
Rockey DC, Housset CN, Friedman SL. Activation-dependent contractility of rat hepatic lipocytes in culture and in vivo
. J Clin Invest 1993;92:1795-804.
Wynn TA. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest 2007;117:524-9.
Khimji AK, Rockey DC. Endothelin-biology and disease. Cell Signal 2010;22:1615-25.
Johnson A, DiPietro LA. Apoptosis and angiogenesis: An evolving mechanism for fibrosis. FASEB J 2013;27:3893-901.
Levine D, Rockey DC, Milner TA, Breuss JM, Fallon JT, Schnapp LM. Expression of the integrin α8β1 during pulmonary and hepatic fibrosis. Am J Pathol 2000;156:1927-35.
Henderson NC, Arnold TD, Katamura Y, Giacomini MM, Rodriguez JD, McCarty JH, et al
. Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat Med 2013;19:1617-24.
Ramachandran P, Iredale JP. Macrophages: Central regulators of hepatic fibrogenesis and fibrosis resolution. J Hepatol 2012;56:1417-9.
Shechter R, Raposo C, London A, Sagi I, Schwartz M. The glial scar-monocyte interplay: A pivotal resolution phase in spinal cord repair. PLoS One 2011;6:e27969.
Du X, Shimizu A, Masuda Y, Kuwahara N, Arai T, Kataoka M, et al
. Involvement of matrix metalloproteinase-2 in the development of renal interstitial fibrosis in mouse obstructive nephropathy. Lab Invest 2012;92:1149-60.
Fallowfield JA, Mizuno M, Kendall TJ, Constandinou CM, Benyon RC, Duffield JS, et al
. Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J Immunol 2007;178:5288-95.
Di Lella S, Sundblad V, Cerliani JP, Guardia CM, Estrin DA, Vasta GR, et al
. When galectins recognize glycans: From biochemistry to physiology and back again. Biochemistry 2011;50:7842-57.
Nangia-Makker P, Honjo Y, Sarvis R, Akahani S, Hogan V, Pienta KJ, et al
. Galectin-3 induces endothelial cell morphogenesis and angiogenesis. Am J Pathol 2000;156:899-909.
Sano H, Hsu DK, Yu L, Apgar JR, Kuwabara I, Yamanaka T, et al
. Human galectin-3 is a novel chemoattractant for monocytes and macrophages. J Immunol 2000;165:2156-64.
Dong R, Zhang M, Hu Q, Zheng S, Soh A, Zheng Y, et al
. Galectin-3 as a novel biomarker for disease diagnosis and a target for therapy (Review). Int J Mol Med 2018;41:599-614.
de Oliveira FL, Gatto M, Bassi N, Luisetto R, Ghirardello A, Punzi L, et al
. Galectin-3 in autoimmunity and autoimmune diseases. Exp Biol Med (Maywood) 2015;240:1019-28.
Pugliese G, Iacobini C, Ricci C, Blasetti Fantauzzi C, Menini S. Galectin-3 in diabetic patients. Clin Chem Lab Med 2014;52:1413-23.
Kim SJ, Lee HW, Gu Kang H, La SH, Choi IJ, Ro JY, et al
. Ablation of galectin-3 induces p27(KIP1)-dependent premature senescence without oncogenic stress. Cell Death Differ 2014;21:1769-79.
Newlaczyl AU, Yu LG. Galectin-3-a jack-of-all-trades in cancer. Cancer Lett 2011;313:123-8.
Chen SC, Kuo PL. The role of galectin-3 in the Kidneys. Int J Mol Sci 2016;17:565.
Saccon F, Gatto M, Ghirardello A, Iaccarino L, Punzi L, Doria A. Role of galectin-3 in autoimmune and non-autoimmune nephropathies. Autoimmun Rev 2017;16:34-47.
Ruvolo PP. Galectin 3 as a guardian of the tumor microenvironment. Biochim Biophys Acta 2016;1863:427-37.
Meijers WC, López-Andrés N. Galectin-3, Cardiac Function, and Fibrosis. Am J Pathol 2016;186:2232-4.
Hu Y, Yéléhé-Okouma M, Ea HK, Jouzeau JY, Reboul P. Galectin-3: A key player in arthritis. Joint Bone Spine 2017;84:15-20.
Meijers WC, van der Velde AR, Pascual-Figal DA, de Boer RA. Galectin-3 and post-myocardial infarction cardiac remodeling. Eur J Pharmacol 2015;763:115-21.
Lala IR, Puschita M, Darabantiu D, Pilat L. Galectin-3 in heart failure pathology-”another brick in the wall”? Acta Cardiol 2015;70:323-31.
Funasaka T, Raz A, Nangia-Makker P. Galectin-3 in angiogenesis and metastasis. Glycobiology 2014;24:886-91.
Li LC, Li J, Gao J. Functions of galectin-3 and its role in fibrotic diseases. J Pharmacol Exp Ther 2014;351:336-43.
McLeod K, Walker JT, Hamilton DW. Galectin-3 regulation of wound healing and fibrotic processes: Insights for chronic skin wound therapeutics. J Cell Commun Signal 2018;12:281-7.
Song X, Qian X, Shen M, Jiang R, Wagner MB, Ding G, et al
. Protein kinase C promotes cardiac fibrosis and heart failure by modulating galectin-3 expression. Biochim Biophys Acta 2015;1853:513-21.
Shen H, Wang J, Min J, Xi W, Gao Y, Yin L, et al
. Activation of TGF-β1/α-SMA/Col I profibrotic pathway in fibroblasts by galectin-3 contributes to atrial fibrosis in experimental models and patients. Cell Physiol Biochem 2018;47:851-63.
Martínez-Martínez E, Brugnolaro C, Ibarrola J, Ravassa S, Buonafine M, López B, et al
. CT-1 (Cardiotrophin-1)-Gal-3 (Galectin-3) Axis in cardiac fibrosis and inflammation: Mechanistic insights and clinical implications. Hypertension 2019;73:602-11.
Besler C, Lang D, Urban D, Rommel KP, von Roeder M, Fengler K, et al
. Plasma and cardiac galectin-3 in patients with heart failure reflects both inflammation and fibrosis: Implications for its use as a biomarker. Circ Heart Fail 2017;10:e003804.
Jaquenod De Giusti C, Ure AE, Rivadeneyra L, Schattner M, Gomez RM. Macrophages and galectin 3 play critical roles in CVB3-induced murine acute myocarditis and chronic fibrosis. J Mol Cell Cardiol 2015;85:58-70.
Vergaro G, Prud'homme M, Fazal L, Merval R, Passino C, Emdin M, et al
. Inhibition of galectin-3 pathway prevents isoproterenol-induced left ventricular dysfunction and fibrosis in mice. Hypertension 2016;67:606-12.
Lax A, Sanchez-Mas J, Asensio-Lopez MC, Fernandez-Del Palacio MJ, Caballero L, Garrido IP, et al
. Mineralocorticoid receptor antagonists modulate galectin-3 and interleukin-33/ST2 signaling in left ventricular systolic dysfunction after acute myocardial infarction. JACC Heart Fail 2015;3:50-8.
Li S, Li S, Hao X, Zhang Y, Deng W. Perindopril and a galectin-3 inhibitor improve ischemic heart failure in rabbits by reducing gal-3 expression and myocardial fibrosis. Front Physiol 2019;10:267.
Martínez-Martínez E, López-Ándres N, Jurado-López R, Rousseau E, Bartolomé MV, Fernández-Celis A, et al
. Galectin-3 participates in cardiovascular remodeling associated with obesity. Hypertension 2015;66:961-9.
Ibarrola J, Matilla L, Martínez-Martínez E, Gueret A, Fernández-Celis A, Henry JP, et al
. Myocardial injury after ischemia/reperfusion is attenuated by pharmacological galectin-3 inhibition. Sci Rep 2019;9:9607.
Ibarrola J, Martínez-Martínez E, Sádaba JR, Arrieta V, García-Peña A, Álvarez V, et al
. Beneficial effects of galectin-3 blockade in vascular and aortic valve alterations in an experimental pressure overload model. Int J Mol Sci 2017;18:1664.
Harrison S, Marri S, Chalasani N, Kohli R, Aronstein W, Thompson G, et al
. Randomised clinical study: GR-MD-02, a galectin-3 inhibitor, vs. placebo in patients having non-alcoholic steatohepatitis with advanced fibrosis. Aliment Pharmacol Ther 2016;44:1183-98.
Tian J, Yang G, Chen HY, Hsu DK, Tomilov A, Olson KA, et al
. Galectin-3 regulates inflammasome activation in cholestatic liver injury. FASEB J 2016;30:4202-13.
Abu-Elsaad NM, Elkashef WF. Modified citrus pectin stops progression of liver fibrosis by inhibiting galectin-3 and inducing apoptosis of stellate cells. Can J Physiol Pharmacol 2016;94:554-62.
Jeftic I, Jovicic N, Pantic J, Arsenijevic N, Lukic ML, Pejnovic N. Galectin-3 ablation enhances liver steatosis, but attenuates inflammation and IL-33-dependent fibrosis in obesogenic mouse model of nonalcoholic steatohepatitis. Mol Med 2015;21:453-65.
Zhou Y, He CH, Yang DS, Nguyen T, Cao Y, Kamle S, et al
. Galectin-3 interacts with the CHI3L1 axis and contributes to Hermansky-Pudlak syndrome lung disease. J Immunol 2018;200:2140-53.
Wang X, Wang Y, Zhang J, Guan X, Chen M, Li Y, et al
. Galectin-3 contributes to vascular fibrosis in monocrotaline-induced pulmonary arterial hypertension rat model. J Biochem Mol Toxicol 2017;31:e21879.
Delaine T, Collins P, MacKinnon A, Sharma G, Stegmayr J, Rajput VK, et al
. Galectin-3-binding glycomimetics that strongly reduce bleomycin-induced lung fibrosis and modulate intracellular glycan recognition. Chembiochem 2016;17:1759-70.
Ho JE, Gao W, Levy D, Santhanakrishnan R, Araki T, Rosas IO, et al
. Galectin-3 Is associated with restrictive lung disease and interstitial lung abnormalities. Am J Respir Crit Care Med 2016;194:77-83.
Cullinane AR, Yeager C, Dorward H, Carmona-Rivera C, Wu HP, Moss J, et al
. Dysregulation of galectin-3. Implications for Hermansky-Pudlak syndrome pulmonary fibrosis. Am J Respir Cell Mol Biol 2014;50:605-13.
Li HY, Yang S, Li JC, Feng JX. Galectin 3 inhibition attenuates renal injury progression in cisplatin-induced nephrotoxicity. Biosci Rep 2018;38:BSR20181803.
Martínez-Martínez E, Ibarrola J, Fernández-Celis A, Calvier L, Leroy C, Cachofeiro V, et al
. Galectin-3 pharmacological inhibition attenuates early renal damage in spontaneously hypertensive rats. J Hypertens 2018;36:368-76.
Martinez-Martinez E, Ibarrola J, Calvier L, Fernandez-Celis A, Leroy C, Cachofeiro V, et al
. Galectin-3 blockade reduces renal fibrosis in two normotensive experimental models of renal damage. PLoS One 2016;11:e0166272.
Calvier L, Martinez-Martinez E, Miana M, Cachofeiro V, Rousseau E, Sádaba JR, et al
. The impact of galectin-3 inhibition on aldosterone-induced cardiac and renal injuries. JACC Heart Fail 2015;3:59-67.
Prud'homme M, Coutrot M, Michel T, Boutin L, Genest M, Poirier F, et al
. Acute kidney injury induces remote cardiac damage and dysfunction through the galectin-3 pathway. JACC Basic Transl Sci 2019;4:717-32.
Harazono Y, Nakajima K, Raz A. Why anti-Bcl-2 clinical trials fail: A solution. Cancer Metastasis Rev 2014;33:285-94.
Harazono Y, Kho DH, Balan V, Nakajima K, Zhang T, Hogan V, et al
. Galectin-3 leads to attenuation of apoptosis through Bax heterodimerization in human thyroid carcinoma cells. Oncotarget 2014;5:9992-10001.
Lee YK, Lin TH, Chang CF, Lo YL. Galectin-3 silencing inhibits epirubicin-induced ATP binding cassette transporters and activates the mitochondrial apoptosis pathway via β-catenin/GSK-3β modulation in colorectal carcinoma. PLoS One 2013;8:e82478.
Ruvolo PP, Ruvolo VR, Benton CB, AlRawi A, Burks JK, Schober W, et al
. Combination of galectin inhibitor GCS-100 and BH3 mimetics eliminates both p53 wild type and p53 null AML cells. Biochim Biophys Acta 2016;1863:562-71.
Xu Y, Li C, Sun J, Li J, Gu X, Xu W. Antitumor effects of galectin-3 inhibition in human renal carcinoma cells. Exp Biol Med (Maywood) 2016;241:1365-73.
Volarevic V, Markovic BS, Jankovic MG, Djokovic B, Jovicic N, Harrell CR, et al
. Galectin 3 protects from cisplatin-induced acute kidney injury by promoting TLR-2-dependent activation of IDO1/Kynurenine pathway in renal DCs. Theranostics 2019;9:5976-6001.
Ruvolo PP, Ruvolo VR, Burks JK, Qiu Y, Wang RY, Shpall EJ, et al
. Role of MSC-derived galectin 3 in the AML microenvironment. Biochim Biophys Acta Mol Cell Res 2018;1865:959-69.
Fortuna-Costa A, Gomes AM, Kozlowski EO, Stelling MP, Pavão MS. Extracellular galectin-3 in tumor progression and metastasis. Front Oncol 2014;4:138.
Xin M, Dong XW, Guo XL. Role of the interaction between galectin-3 and cell adhesion molecules in cancer metastasis. Biomed Pharmacother 2015;69:179-85.
Tanida S, Mori Y, Ishida A, Akita K, Nakada H. Galectin-3 binds to MUC1-N-terminal domain and triggers recruitment of β-catenin in MUC1-expressing mouse 3T3 cells. Biochim Biophys Acta 2014;1840:1790-7.
Reticker-Flynn NE, Bhatia SN. Aberrant glycosylation promotes lung cancer metastasis through adhesion to galectins in the metastatic niche. Cancer Discov 2015;5:168-81.
Glinskii OV, Li F, Wilson LS, Barnes S, Rittenhouse-Olson K, Barchi JJ Jr., et al
. Endothelial integrin α3β1 stabilizes carbohydrate-mediated tumor/endothelial cell adhesion and induces macromolecular signaling complex formation at the endothelial cell membrane. Oncotarget 2014;5:1382-9.
Arad U, Madar-Balakirski N, Angel-Korman A, Amir S, Tzadok S, Segal O, et al
. Galectin-3 is a sensor-regulator of toll-like receptor pathways in synovial fibroblasts. Cytokine 2015;73:30-5.
Markowska AI, Liu FT, Panjwani N. Galectin-3 is an important mediator of VEGF- and bFGF-mediated angiogenic response. J Exp Med 2010;207:1981-93.
Machado CM, Andrade LN, Teixeira VR, Costa FF, Melo CM, dos Santos SN, et al
. Galectin-3 disruption impaired tumoral angiogenesis by reducing VEGF secretion from TGFβ1-induced macrophages. Cancer Med 2014;3:201-14.
Dos Santos SN, Sheldon H, Pereira JX, Paluch C, Bridges EM, El-Cheikh MC, et al
. Galectin-3 acts as an angiogenic switch to induce tumor angiogenesis via Jagged-1/Notch activation. Oncotarget 2017;8:49484-501.
Chen WS, Cao Z, Leffler H, Nilsson UJ, Panjwani N. Galectin-3 inhibition by a small-molecule inhibitor reduces both pathological corneal neovascularization and fibrosis. Invest Ophthalmol Vis Sci 2017;58:9-20.
Mirandola L, Yu Y, Cannon MJ, Jenkins MR, Rahman RL, Nguyen DD, et al
. Galectin-3 inhibition suppresses drug resistance, motility, invasion and angiogenic potential in ovarian cancer. Gynecol Oncol 2014;135:573-9.
Duckworth CA, Guimond SE, Sindrewicz P, Hughes AJ, French NS, Lian LY, et al
. Chemically modified, non-anticoagulant heparin derivatives are potent galectin-3 binding inhibitors and inhibit circulating galectin-3-promoted metastasis. Oncotarget 2015;6:23671-87.
Walker JT, Kim SS, Michelsons S, Creber K, Elliott CG, Leask A, et al
. Cell–matrix interactions governing skin repair: Matricellular proteins as diverse modulators of cell function. Res Rep Biochem 2015;5:73-88.
Ochieng J, Furtak V, Lukyanov P. Extracellular functions of galectin-3. Glycoconj J 2002;19:527-35.
Sharma UC, Pokharel S, van Brakel TJ, van Berlo JH, Cleutjens JP, Schroen B, et al
. Galectin-3 marks activated macrophages in failure-prone hypertrophied hearts and contributes to cardiac dysfunction. Circulation 2004;110:3121-8.
Yu L, Ruifrok WP, Meissner M, Bos EM, van Goor H, Sanjabi B, et al
. Genetic and pharmacological inhibition of galectin-3 prevents cardiac remodeling by interfering with myocardial fibrogenesis. Circ Heart Fail 2013;6:107-17.
Papaspyridonos M, McNeill E, de Bono JP, Smith A, Burnand KG, Channon KM, et al
. Galectin-3 is an amplifier of inflammation in atherosclerotic plaque progression through macrophage activation and monocyte chemoattraction. Arterioscler Thromb Vasc Biol 2008;28:433-40.
Martínez-Martínez E, Calvier L, Fernández-Celis A, Rousseau E, Jurado-López R, Rossoni LV, et al
. Galectin-3 blockade inhibits cardiac inflammation and fibrosis in experimental hyperaldosteronism and hypertension. Hypertension 2015;66:767-75.
He J, Li X, Luo H, Li T, Zhao L, Qi Q, et al
. Galectin-3 mediates the pulmonary arterial hypertension-induced right ventricular remodeling through interacting with NADPH oxidase 4. J Am Soc Hypertens 2017;11:275-8900.
Ibarrola J, Arrieta V, Sádaba R, Martinez-Martinez E, Garcia-Peña A, Alvarez V, et al
. Galectin-3 down-regulates antioxidant peroxiredoxin-4 in human cardiac fibroblasts: A new pathway to induce cardiac damage. Clin Sci (Lond) 2018;132:1471-85.
Zannad F, Alla F, Dousset B, Perez A, Pitt B. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: Insights from the randomized aldactone evaluation study (RALES). Rales Investigators. Circulation 2000;102:2700-6.
Calvier L, Miana M, Reboul P, Cachofeiro V, Martinez-Martinez E, de Boer RA, et al
. Galectin-3 mediates aldosterone-induced vascular fibrosis. Arterioscler Thromb Vasc Biol 2013;33:67-75.
Martínez-Martínez E, Calvier L, Rossignol P, Rousseau E, Fernández-Celis A, Jurado-López R, et al
. Galectin-3 inhibition prevents adipose tissue remodelling in obesity. Int J Obes (Lond) 2016;40:1034-8.
Azibani F, Benard L, Schlossarek S, Merval R, Tournoux F, Fazal L, et al
. Aldosterone inhibits antifibrotic factors in mouse hypertensive heart. Hypertension 2012;59:1179-87.
Lin YH, Chou CH, Wu XM, Chang YY, Hung CS, Chen YH, et al
. Aldosterone induced galectin-3 secretion in vitro
and in vivo
: From cells to humans. PLoS One 2014;9:e95254.
van den Berg TN, Meijers WC, Donders AR, Van Herwaarden AE, Rongen GA, de Boer RA, et al
. Plasma galectin-3 concentrations in patients with primary aldosteronism. J Hypertens 2017;35:1849-56.
van der Velde AR, Gullestad L, Ueland T, Aukrust P, Guo Y, Adourian A, et al
. Prognostic value of changes in galectin-3 levels over time in patients with heart failure: Data from CORONA and COACH. Circ Heart Fail 2013;6:219-26.
Zannad F. Aldosterone and heart failure. Eur Heart J 1995;16 Suppl N: 98-102.
Lopez-Andrès N, Rossignol P, Iraqi W, Fay R, Nuée J, Ghio S, et al
. Association of galectin-3 and fibrosis markers with long-term cardiovascular outcomes in patients with heart failure, left ventricular dysfunction, and dyssynchrony: Insights from the CARE-HF (Cardiac Resynchronization in Heart Failure) trial. Eur J Heart Fail 2012;14:74-81.
Arrieta V, Martinez-Martinez E, Ibarrola J, Alvarez V, Sádaba R, Garcia-Peña A, et al
. A role for galectin-3 in the development of early molecular alterations in short-term aortic stenosis. Clin Sci (Lond) 2017;131:935-49.
Calvier L, Legchenko E, Grimm L, Sallmon H, Hatch A, Plouffe BD, et al
. Galectin-3 and aldosterone as potential tandem biomarkers in pulmonary arterial hypertension. Heart 2016;102:390-6.
Koukoui F, Desmoulin F, Galinier M, Barutaut M, Caubère C, Evaristi MF, et al
. The prognostic value of plasma galectin-3 in chronic heart failure patients is maintained when treated with mineralocorticoid receptor antagonists. PLoS One 2015;10:e0119160.
Fiuzat M, Schulte PJ, Felker M, Ahmad T, Neely M, Adams KF, et al
. Relationship between galectin-3 levels and mineralocorticoid receptor antagonist use in heart failure: Analysis from HF-ACTION. J Card Fail 2014;20:38-44.
Gandhi PU, Motiwala SR, Belcher AM, Gaggin HK, Weiner RB, Baggish AL, et al
. Galectin-3 and mineralocorticoid receptor antagonist use in patients with chronic heart failure due to left ventricular systolic dysfunction. Am Heart J 2015;169:404-11000.
Sciacchitano S, Lavra L, Morgante A, Ulivieri A, Magi F, De Francesco GP, et al.
Galectin-3: One molecule for an alphabet of diseases, from A to Z. Int J Mol Sci 2018;19:379.
Peacock WF, DiSomma S. Emergency department use of galectin-3. Crit Pathw Cardiol 2014;13:73-7.
Desmedt V, Desmedt S, Delanghe JR, Speeckaert R, Speeckaert MM. Galectin-3 in renal pathology: More than just an innocent bystander? Am J Nephrol 2016;43:305-17.
[Figure 1], [Figure 2]