Table of Contents
Year : 2016  |  Volume : 1  |  Issue : 3  |  Page : 28-36

The role of Galectin-3 in cardiac remodeling

Department of Cardiology, Xiangya Hospital, Central South University, Changsha, China

Date of Web Publication26-Dec-2018

Correspondence Address:
Zaixin Yu
Department of Cardiology, Xiangya Hospital, Central South University, 87 Xiangya Road, 410008 Changsha
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2470-7511.248355

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Galectin-3 is a member of the β-galactoside-binding galectins and is characterized by a carbohydrate recognition domain. Galectin-3 regulates the various biological processes such as cell growth, differentiation, immune function, cancer metastasis, apoptosis, inflammation, and fibrosis. Current clinical and experimental evidence repeatedly suggest that galectin-3 expression is upregulated in various stages of cardiac remodeling in cardiovascular diseases. Studies also find that either genetic or pharmacological inhibition of galectin-3 can slow the progression of myocardial inflammation, reduce collagen production, attenuate cardiac remodeling, and ameliorate cardiac function. Altogether these data support further scientific attention for galectin-3 to clarify its precise mechanisms in causing or aggravating cardiac remodeling in cardiovascular diseases. This reviews presents a general survey on galectin-3 as a regulatory molecule affecting the various stages from acute to chronic inflammation and cardiac fibrogenesis in common types of cardiovascular diseases, as well as its potential role in the diagnosis, risk stratification, and treatment of cardiovascular diseases.

Keywords: Cardiac remodeling, cardiovascular diseases, galectin-3, myocardial fibrosis

How to cite this article:
He J, Yu Z. The role of Galectin-3 in cardiac remodeling. Cardiol Plus 2016;1:28-36

How to cite this URL:
He J, Yu Z. The role of Galectin-3 in cardiac remodeling. Cardiol Plus [serial online] 2016 [cited 2022 Jan 19];1:28-36. Available from:

  Introduction of Galectin-3 Top

Galectin-3 is a member of soluble β-galactoside-binding animal lectins of 32-35 kDa. It is mainly expressed and secreted by macrophages but is also expressed in fibroblasts, mast cells, and neutrophils.[1],[2] Galectin-3 is the only one discovered in mammals.[3] Galectin-3 is expressed in the cytoplasm, nucleus, and cell membrane making it possible to play important roles in modulating inflammatory and immunological responses. Galectin-3 regulates numerous biological processes through its carbohydrate recognition domain using carbohydrate-independent mechanisms.[4],[5] Galectin-3 functions by binding to different ligands, for example, to inflammatory factors (interleukin [IL]-4, CD45 and CD98) to accelerate inflammation and cell apoptosis, or the extracellular matrix to promote fibrosis.[6] Galectin-3 takes part in multiple pathophysiological steps in regulating inflammation, fibrosis, immunity, and cancer metastasis. Critically, inflammation and fibrosis play an indispensable role in myocardial remodeling.[7] Previous studies indicate that galectin-3 is a central component in the development of myocardial and vascular fibrosis,[8],[9] likely by activating transforming growth factor (TGF)-β–mediated myofibroblast and stimulating matrix production.[10],[11]

Structures and distributions

The galectin-3 is widely distributed and is found in different organs including the lungs, heart, stomach, colon, adrenal gland, uterus, and ovaries.[12] The galectin-3 gene, LGALS3, is located on chromosome 14. Galectin-3 is the only chimaera-type galectin in the galectin family with a molecular weight of 29–35 kDa and is constituted of 251 amino acid residues and 2 different domains.[6] The N-terminal domain comprised 120 amino acids contains a tandem repetitive short amino acid segment of proline, glycine, alanine, and tyrosine. Parts of N-terminal domains are crosslinked to C-terminal carbohydrate-recognition domains. Although the C-terminal domain could directly modulate the activity of lectin, both the N-terminal and the C-terminal domain together are responsible for the full bioactivity of galectin-3.[6] It can be secreted by nonclassical secretory pathways[13] and can bind to the receptors on the surface of cells to initiate different functions. Galectin-3 is a unique, chimeric protein consisting of three distinct structural motifs enabling it to interact with a plethora of ligands and modulate diverse functions such as cell growth, adhesion, migration, invasion, angiogenesis, immune function, apoptosis, and endocytosis emphasizing its significance in the process of tumor progression.[14]


Galectin-3 is predominantly located in the cytoplasm where it can be secreted extracellularly or shuttle into the nucleus.[15] Galectin-3 participates in various pathophysiological processes, including cell proliferation, apoptosis, adhesion, and angiogenesis, however, its most essential function is to trigger inflammation and fibrosis [Figure 1].[16] Extracellular galectin-3 mediates cell migration, cell adhesion, cell–cell interactions through high-affinity binding with galactose-containing glycoproteins on the cell surface and is also important for the interaction between epithelial cells and extracellular matrix.[15],[17] Cytoplasmic galectin-3 modulates cell survival by its anti-apoptotic activity and regulates several signal transduction pathways. Nuclear galectin-3 has been associated with pre-mRNA splicing and gene expression and can promote cell proliferation.[15],[18]
Figure 1: The action of galectin-3 in the cells

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Galectin-3 is responsible for the process of cellular transport, activation, and release of cytokines as well as infiltration, activation, and removal of inflammatory cells.[19] Current clinical and experimental evidence shows that galectin-3 is implicated in a number of diseases such as renal fibrosis, heart failure (HF), obesity, impaired glucose metabolism, and cancer metabolism.[17],[20],[21],[22] Galectin-3 has also been implicated in the pathogenesis of cardiac remodeling, infections, and various autoimmune and inflammatory processes.[23] When the heart is overloaded or injured, monocyte-macrophages secrete large amounts of galectin-3 into the extracellular matrix. Galectin-3 could then activate the TGF-β/Smad3 pathway and turn quiescent fibroblasts into myofibroblasts. Meanwhile, multiple extracellular matrix proteins such as cytoskeletal proteins, laminin, fibronectin, elastin, and collagen IV fibers are being produced.[2],[12]

  Role of Galectin-3 in Cardiovascular Diseases Top

Galectin-3 and heart failure

Galectin-3 has been widely studied for its correlation with myocardial fibrosis and cardiac remodeling in cardiovascular diseases [Figure 2]. HF is the end stage of various cardiovascular diseases including coronary artery disease, hypertension, valvular heart disease, infection, and cardiomyopathy. HF occurs when the heart is unable to pump sufficiently to maintain blood flow and is most commonly caused by structural or functional changes of the heart. HF has a high morbidity and mortality rate and is still one of the most prevalent and challenging medical issues in the world. While the extent of cardiac structural changes could largely influence the cardiac function, slowing the progression of cardiac remodeling could possibly become a new therapeutic target for HF.
Figure 2: Galectin-3 and cardiovascular diseases

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Galectin-3 could possibly become one of the most accurate biomarkers for evaluating short- and long-term prognosis of HF patients. As shown in a recent study, an increased level of galectin-3 is closely associated with a higher mortality rate and more adverse effects in HF patients. In the past few years, clinical studies, such as COACH,[24] CORONA[25] and HF-ACTION,[26] have shown that, the galectin-3 in combination with NT-proBNP could better predict the prognosis of HF than using NT-proBNP alone.[27] Researchers identified that a higher level of serum galectin-3 is associated with a greater risk of adverse cardiovascular events and a constant increase in galectin-3 levels may also be a risk factor for HF.[28] With approximately half of the patients with acute HF with a preserved ejection fraction,[29] the galectin-3 positively correlated with the severity of the diastolic function and the left ventricular (LV) wall thickness. In additiona, compared to NT-proBNP, troponin, C-reaction protein, and other biomarkers of HF, galectin-3 showed the least biological variability among the patients with chronic HF.[27] In addition to galectin-3's role as a risk factor in HF, it also could guide treatment and medical choices. A recent study has showed that lower serum galectin-3 levels improve the outcome of β-antagonists, but worsen the effect of aldosterone receptor antagonists.[30]

The initial observations by Sharma et al.[8] were to explore the role of galectin-3 in the cardiac remodeling of HF using HF-prone Ren-2 rats. They found that the expression of galectin-3 was predominantly increased during the transitional stage of HF from a compensated to a decompensated stage. The galectin-3 level correlated with the number of macrophages and fibroblasts. In addition, there was a high level of galectin-3 expression in the areas with abundant amounts of extracellular matrix deposition. After infusion of galectin-3 into the pericardial sac in rats, the extent of cardiac remodeling and myocardial fibrosis was aggravated compared to control animals, which was accompanied by decreased cardiac function, depressed cardiac output and lower LV ejection fraction.[8] In the same pericardial infusion rat models, Liu et al.[31] co-infused galectin-3 along with galectin-3 inhibitors (Ac-SDKP) into the pericardial sac. This experiment indicated that Ac-SDKP could alleviate the fibrotic effect induced by galectin-3 on myocardial fibrosis and cardiac remodeling.[31] Subsequently, Yu et al.[1] compared two mice groups, galectin-3 knock-out mice (KO groups) and wild-type mice as controls (WT groups). Both groups of mice were either infused with angiotensin II for 2 weeks or given transaortic constriction surgery for 4 weeks.[1] When the mice models were set up successfully, all mice were presented with left HF and cardiac remodeling. However, the KO groups showed a less severe myocardial interstitial fibrosis when compared to the controls. These results indicated that knocking-out galectin-3 not only neutralized fibrosis and inflammation but also alleviate cardiac dysfunction to a certain extent.[1]

The previous clinical and experimental studies have indicated that galectin-3 is a regulatory molecule affecting various stages of cardiac remodeling. A new study by Coromilas et al.[32] examined the utility of galectin-3 as a marker of the severity of HF and determined galectin-3 levels in response to LV assist device (LVAD) implantation or heart transplantation (HTx) and revealed its use as a prognostic indicator. They compared the serum galectin-3 levels in patients with stable HF, severe HF, at 3 and 6 months post-LVAD and at LVAD explantation, patients following HTx and also healthy controls. The results showed that galectin-3 levels increase with the severity of HF, exhibit dynamic changes during mechanical unloading, and predicts survival post-LVAD. Following LVAD implantation, galectin-3 levels are initially lower at 3 months and 6 months post-LVAD but are higher compared to pre-LVAD patients.[32] In addition, galectin-3 levels >30 ng/ml are associated with lower survival post-LVAD placement. Following HTx, galectin-3 levels are lower compared to pre-HTx patients. Galectin-3 can possibly serve as a new biomarker and prognostic indicator in patients with HF, during LVAD support and following HTx.[32] Moreover, galectin-3 levels are suggested to improve care quality.[33] A study has found that the effectiveness of multidisciplinary disease management programs (MDP) for HF patients at high risk was inadequate, especially for those with high galectin-3 levels (≥17.9 ng/ml).[33] Further, the analysis identified characteristics of MDP nonresponders and better integrated advanced care plans based on strategies guided by galectin-3 levels.[33]

While it has been supported by most studies that galectin-3 and cardiac remodeling are related, some researchers held a skeptical opinion. These researchers found that levels of galectin-3 and some other fibrotic markers (PICP, PIIINP) increased in serum. Furthermore, galectin-3 and collagen I, III expression was upregulated in myocardial tissue of HF patients.[34] However, there was no direct correlation found between those fibrotic markers and galectin-3 levels.[34]

In summary, it has been proved that the genetic and pharmacological inhibition of galectin-3 could effectively suppress myocardial fibrosis and prevent cardiac remodeling in HF animal models. Galectin-3 has a high possibility to become a new biomarker and prognostic indicator in patients with HF. However, further research is still needed to confirm the exact role of galectin-3 in HF patients and the possible mechanisms and signaling pathways involved.

Galectin-3 and cardiomyopathy

Viral myocarditis is a virus-related inflammation of myocardium and is the most common infectious myocarditis. Acute myocarditis is thought to be an autoimmune disease and is mostly self-limiting. However, in some patients, it may present with severe myocardial injury and can be accompanied by a postviral immune-mediated response, which would eventually lead to dilated cardiomyopathy (DCM) and HF.[35] Coxsackievirus B3 (CVB3), a globally prevalent enterovirus, belongs to the Picornavirida family. It is well known for its close relationship to viral myocarditis.[35] Studies have shown that macrophages and galectin-3 play an important role in the pathophysiologic process of CVB3-induced cardiac inflammation and fibrosis.[36] In CVB3-induced myocarditic mice models, it has been found there was an upregulation of galectin-3 expression in myocardial tissue.[36] Moreover, after pharmacological or genetic inhibition of galectin-3, the degree of myocardial necrosis, acute inflammation, and chronic myocardial fibrosis could be suppressed. However, the study also pointed out that cardiac inflammation and fibrosis levels were similar after macrophages depletion and that galectin-3 seems to have no effect on CVB3 replication.[36]

Hypertrophic cardiomyopathy (HCM), a primary disease of the myocardium, is characterized by myocardial hypertrophy. The occurrence of cardiac fibrosis and irreversible ventricular structure change is significantly contributes to sudden cardiac death in patients with HCM.[37] In a case–control study by Yakar et al.[38] the relationship between galectin-3 levels and LV function in 40 HCM patients and 35 age-matched healthy controls were analyzed and compared. This study found that galectin-3 levels were significantly up-regulated in patients with HCM compared to controls.[38] Moreover, the galectin-3 levels positively correlated to the thickness of the interventricular septum and LV mass index. However, while LV global longitudinal strain (GLS) and strain rate (SR) could reflect LV diastolic and systolic function, this study found no obvious relationship between GLS, SR, and galectin-3 levels.[38] The galectin-3 level was also not associated with the magnitude of LV outflow tract obstruction. It was, therefore, concluded that galectin-3 level was associated with the LV hypertrophy degree, but not with the LV diastolic and systolic dysfunction.

DCM is a group of diseases that primarily affect the myocardium. In DCM, a portion of the myocardium is dilated often without any obvious cause. Left or right ventricular systolic pump dysfunction can lead to progressive cardiac enlargement and hypertrophy.[39] DCM is the most common form of nonischemic cardiomyopathy.[40] LV fibrosis, assessed by late gadolinium enhancement (LGE) in cardiac magnetic resonance imaging (MRI), is a marker of LVR and holds prognostic value in nonischemic DCM. A study showed that patients with LGE had higher galectin-3 levels than those without.[40] Among multivariate analysis, galectin-3 maintained its predictive value together with sex, hypertension, disease duration, and right ventricular ejection fraction.[40] In patients with nonischemic DCM, it was found that serum galectin-3 levels are associated with LGE-assessed myocardial replacement fibrosis. This indicated that galectin-3 is involved in cardiac fibrosis and remodeling in NICM and that assaying for it may help to select subgroups at higher risk.[40]

Diabetic cardiomyopathy is a disorder of the myocardium in patients with diabetes.[41] Most HF in people with diabetes results from coronary artery disease, so diabetic cardiomyopathy is only diagnosed when there is no coronary artery disease to explain the cardiac remodeling.[42] Diabetic cardiomyopathy is characterized structurally and functionally by ventricular dilation, enlargement of cardiomyocytes, prominent interstitial fibrosis, and decreased or preserved systolic function in the presence of a diastolic dysfunction.[41],[43] Galectin-3 has been involved in glucose metabolism.[22] A recent study has found that galectin-3 is elevated in diabetic patients with mild depressed ejection fraction (mdEF) (LVEF 47.0 ± 6.9) and correlates with diminished GLS.[44] This study indicated that GLS and galectin-3 levels could be early markers of LV dysfunction and evidence of diabetic cardiomyopathy.[44]

To conclude, we suggest that galectin-3 plays a critical role in the pathophysiologic process of acute cardiac inflammation, chronic fibrosis, and cardiac remodeling in cardiomyopathies. Inhibition of galectin-3 could possibly alleviate acute myocardial inflammation and ameliorate cardiac remodeling. Galectin-3 may also be a new biomarker for the diagnosis and treatment of cardiomyopathies.

Galectin-3 and coronary heart disease

Coronary heart disease (CHD), also known as ischemic heart disease, involves inflammation throughout its entire developmental process. Galectin-3, a major inflammatory signal and promoter, can activate reduced-coenzyme, increase neutrophil superoxide production, stimulate outbreak of the respiratory chain, and trigger oxidative-stress reactions leading to an increase in uptake of ox-LDL by vascular endothelial cells, macrophages, and smooth muscle cells, eventually causing the proliferation of foam cells and promoting atherosclerosis.[45] In a case–control study, galectin-3 levels in patients with CHD were shown to be significantly higher than that in the control group. It was found that the serum galectin-3 level had a positively correlated with the severity of coronary artery stenosis, number of vessels involved, and serum C-reactive protein levels.[46]

CHDs include stable angina, unstable angina, myocardial infarction (MI), and sudden cardiac death. MI is the most severe form of CHD, is caused by myocardial necrosis led by a drastic reduction or interruption of blood flow in the coronary artery. LV remodeling (LVR) is progressive functional and structural change in the left ventricle and is induced by myocardial injury and necrosis.[47] Although a recent study showed that serum galectin-3 levels had no impact in the acute phase of myocardial ischemia, it still somewhat related to the infarct size and LVR in previous MIs.[48] Sanchez-Mas et al.[49] studied galectin-3 expression in the myocardium in MI using classic MI rat models. After permanent ligation of the left anterior descending coronary artery, rats were sacrificed at 1, 2, 4, 12, and 24 weeks post-MI. This study showed that galectin-3 expression was upregulated in the sites of infarction, reached its maximum at 1 week post-MI, which was then followed by a gradual decrease in the following weeks.[49] Other than galectin-3, various extracellular matrix and fibrotic markers such as collagen I, collagen III, and TIMP-1 also increased in expression. Although there was also an increase of galectin-3 in the non-infarcted area, its maximal level did not appear until week 24.[49]

Although the role of galectin-3 in atherosclerosis progression has not been clearly defined, a study has shown that galectin-3 is an independent risk factor of CHD occurrence.[50] Galectin-3 levels were significantly higher in patients diagnosed with MI or CHD compared to control. Patients with three-vessel disease had higher levels of galectin-3 than patients with 1-or 2-vessel disease.[50] During mid-term follow-up among MI patients, galectin-3 concentration >8.7 ng/ml was used as an independent predictive indicator of increased risk of all-cause mortality in patients. In the group of MI patients who died during the follow-up, a significantly higher concentration of galectin-3 levels was found.[50] In recent years, a number of studies[49],[51],[52] have indicated that galectin-3 is an active participator in the remodeling process following MI. In early phases, galectin-3 is involved in the reparative process of infarct areas, explaining its higher expression in those areas. A study showed that the genetic disruption of galectin-3 could cause abnormal cardiac remodeling and high mortality rate in the early phase.[51],[52] Therefore, it is argued that the galectin-3 is essential for the maintenance of ventricular structure and function in the early phase of MI. On the contrary, in the later phase, galectin-3 would trigger chronic inflammation and cardiac fibrosis processes potentially leading to adverse ventricular remodeling.[51]

Despite modern reperfusion therapies, LVR still happens frequently after ST-elevated MI (STEMI), which represents an important predictor of mortality and HF after MI.[53] A study has indicated that galectin-3 levels were independently associated to an increased risk of LVR after MI.[54] The study showed that serum galectin-3 levels measured during hospitalization could be clinically significant in predicting LVR among patients admitted with anterior STEMI treated by reperfusion therapies.[54] LVR was defined as a ≥15% increase in LV end-systolic volume. The results showed that 26 of the 92 survivors (28.3%) developed LVR (LVR+) during 6 months of follow-up.[54] LVR+ patients had higher galectin-3 levels at baseline, 1 and 6 months compared to LVR-. By either univariable logistic regression or multivariable analysis, LV end-diastolic volume and galectin-3 levels were independently associated to an increased risk of LVR and predicted LVR. This result indicated that galectin-3 could be regarded as a new independent predictor of prognosis after MI.[54] Aside from galectin-3, galectin-3 binding protein (Gal-3BP) is a secreted protein associated with inflammation and carotid atherosclerosis.[55] A new study has found that the serum GAl-3BP levels of 149 confirmed CHD patients (stenosis grade >20%) were not different from patients without CHD.[55] However, over a follow-up time of up to 4.4 years, the analysis revealed that high Gal-3BP levels were significantly associated with long-term mortality (P < 0.001), and this association was independent of cardiovascular risk factors.[55] Further analysis showed that Gal-3BP levels were significantly related to body mass index and high-sensitivity C-reactive protein levels indicating an association with metabolic and inflammatory distress.[55] It has been confirmed that high serum galectin-3 binding protein levels are associated with long-term mortality, but whether galectin-3 could be a marker of cardiac mortality or unstable plaque morphology still requires further research.

The role of galectin-3 in early or late phases following MI can be quite different and controversial. It is certain that galectin-3 correlates with the extent of myocardial inflammation, cardiac fibrosis and LVR following MI. Serum galectin-3 concentrations could be regarded as an independent predictor of prognosis after MI.

Galectin-3 and hypertension

Hypertension is normally a chronic medical condition characterized by elevated arterial blood pressure. Hypertensive cardiac remodeling begins with inflammation, increased deposition of extracellular matrix proteins, followed by the formation of myocardial fibrosis and finally cardiac dysfunction.[56] A study has shown that serum galectin-3 levels increase in patients with hypertension; however, it is more obvious in patients with LV hypertrophy. Therefore, galectin-3 as a valuable biomarker for early cardiac remodeling is independently correlated with LVR.[57] Only LV mass was independently correlated with serum galectin-3 levels in patients with hypertension. Therefore, galectin-3 is independently correlated with LV myocardial remodeling and can be regarded as a valuable biomarker of early cardiac remodeling of hypertension.

Aldosteronism is regarded as the most common cause of secondary hypertension. Patients with primary aldosteronism are associated with increased myocardial inflammation and myocardial fibrosis.[58] A previous study has found that aldosterone can induce the secretion of galectin-3.[58] Galectin-3 is one of the most important mediators between macrophage activation and myocardial fibrosis. In a prospective clinical pilot follow-up study, serum galectin-3 was significantly higher in an aldosterone-producing adenoma group.[59] Moreover, both the degree of myocardial fibrosis and serum galectin-3 levels recovered to after adrenalectomy.[59] Azibani et al.[60] first stated that hyper-aldosteronism increases the number of inflammatory factors, including galectin-3, and worsens hypertension-induced fibrosis. However, the role of galectin-3 in the aldosterone-induced inflammation is still unclear.[60] Calvier et al.[9],[61] then proved the role of galectin-3 in aldosterone-induced vascular and cardiac fibrosis. Subsequent studies[62] found that blood pressure, myocardial fibrosis level, and cardiac galectin-3 expression is increased in hypertensive rat models induced by aldosterone-salt treatment.[62] Interestingly, there is a positive correlation between pro-inflammatory, pro-fibrotic factors, and galectin-3 levels.[62] In addition, after administration of galectin-3 pharmacological inhibitors (modified citrus pectin) to aldosterone-salt–treated rats, the levels of cardiac inflammation and fibrosis induced by aldosterone were clearly attenuated whereas galectin-3 blockade did not modify blood pressure levels.[62]

In an in vitro study[63] where aldosterone was added to human cardiac fibroblasts, it was found that cellular galectin-3 expression significantly upregulated after 24 h, along with an increase in the secretion of intracellular pro-inflammatory markers such as IL-6 and CCL2 and extracellular matrix components such as collagen type I, collagen type III and fibronectin.[63] Moreover, after using the aldosterone-receptor antagonist, spironolactone, it was found that galectin-3 levels induced by aldosterone were also suppressed in human cardiac fibroblasts.[63]

The latest research by Zhang et al.[64] observed the impact of valsartan on cardiac and renal hypertrophy and galectin-3 changes in the cardiorenal syndrome models. It was found that cardiac and renal hypertrophies were significantly alleviated using valsartan alone; however, the extent of cardiac enlargement was not affected. Expression of galectin-3 and myocardial extracellular matrix collagen I were down-regulated after using valsartan, indicating that galectin-3 might associate with the cardiac remodeling in the cardiorenal syndrome models.[64] A new study also has indicated that galectin-3 may be a new biomarker for risk classification among hypertension patient group.[65] Galectin-3 is a marker associated with myocardial fibrosis and LV myocardial index (LVMI). Myocardial fibrosis and LVMI were reported to be associated with microvolt T-wave alternans (MTWA) positivity.[65] Among hypertensive patients, it is found that increased galectin-3 levels are associated with ambulatory ECG-based MTWA positivity, decreased estimated glomerular filtration rate, and increased LVMI.[65] These associations may be used for risk classification in the sustained systodiastolic hypertension patient group.

Above all, in primary hypertension or aldosteronism-induced secondary hypertension, the galectin-3 level is positively associated with the extent of LVR. Using pharmacological galectin-3 inhibitors could possibly alleviate the inflammation and fibrosis caused by hypertension, and thus, slowing down the progression of disease.

Galectin-3 and pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is an increase in blood pressure in the pulmonary artery. Long-term PAH could cause changes in the right contractile function, hypertrophy, chamber size and the extracellular matrix, eventually resulting in the right HF. Traditional biological markers (BNP or NT-proBNP) for evaluating the prognosis of PAH are not specific to the right ventricular function and are unreliable due to other factors such as age, sex, and obesity.[66] Many studies have shown that galectin-3 is a mediator and new biomarker in myocardial inflammation and fibrosis. However, most researchers focus primarily its role on the left ventricle remodeling; there are few studies that focus on its ability to reflect pulmonary vascular and right ventricle remodeling.

In patients with Tetralogy of Fallot,[67] an increase in serum N-terminal propeptide of type III collagen type (PIIINP), tissue inhibitor of metalloproteinase-1 (TIMP-1), and hyaluronic acid (HA) levels were correlated with PAH as well as right ventricular remodeling.[67] Subsequently, Fenster et al.[68] compared 15 PAH patients and 10 age-matched healthy people. The study found elevated serum galectin-3, PIIINP, TIMP-1, and HA levels in PAH patients. The galectin-3 levels were found to be positively related to levels of the serum the ECM markers TIMP-1 and HA, but not with PIIINP.[68] Moreover, this study found a correlation between the galectin-3 levels with right ventricular ejection fraction, end-diastolic volume index, end-systolic volume index, and systolic pressure.[68] Galectin-3 levels, therefore, have the potential to indicate right ventricular function and the morphological changes. A recent study by Calvier et al.[69] found that serum galectin-3 levels were elevated in both idiopathic PAH and connective tissue related PAH patients; however, the aldosterone level only significantly increased in patients with idiopathic PAH. According to this point of fact, we suggest that galectin-3 combined with aldosterone as biomarkers might help differentiate different subtypes of PAH.[69] In addition, the serum levels of aldosterone, galectin-3, and NT-proBNP were all significantly higher in PAH patients, who had WHO functional Class II-III, versus PAH patients who had PAH functional class I and controls.[69]

A previous study has shown that elevated platelet-derived growth factor (PDGF) level has been implicated in the patients with PAH.[70] PDGF contributes to the progression of PAH by inducing cell proliferation and migration, as well as inhibiting cell apoptosis of pulmonary arterial smooth muscle cells (PASMCs).[70],[71] A new study has found that expression of galectin-3 protein was induced by PDGF in a dose-and a time-dependent manner.[72] Moreover, galectin-3 mediated the effects of PDGF on PASMC proliferation, apoptosis, and migration and these effects of PDGF on PASMC were attenuated by galectin-3 knockdown.[72] Galectin-3 may play role in the pathophysiological mechanisms of PAH.[72]

Researchers have highlighted the possible correlation between galectin-3 and PAH-induced right ventricular functional status and structural changes. Galectin-3 might become a new biomarker for estimating the severity of the right ventricular dysfunction and progression of PAH.

Galectin-3 and atrial fibrillation

Atrial fibrillation (AF) is an abnormal heart rhythm characterized by rapid and irregular beating and is the most common and serious arrhythmia.[73] AF is closely linked to several cardiovascular sequelae including mortality, stroke, and HF.[73] Particularly, atrial interstitial fibrosis appears to be a key contributor to AF substrate.[74] Left atrial (LA) interstitial fibrosis is known to have a role in the initiation and maintenance of AF.[74] The exact pathways leading to atrial fibrosis remains unknown.

Galectin-3 promotes fibrosis and cardiac remodeling and is a well-established cause of arrhythmias. Most studies focus on the association between galectin-3 levels and cardiac fibrosis in HF. The role of galectin-3 in the pathophysiology of AF has not yet been thoroughly evaluated. Sonmez et al.[75] were the first to investigate whether serum levels of novel fibro-inflammation biomarkers differ in patients with AF compared to patients with sinus rhythm.[75] The results showed that new circulating remodeling markers such as galectin-3, MMP-9, and PIIINP levels were significantly higher in AF patients.[75] Moreover, galectin-3, MMP-9, and PIIINP had a strong positive correlation with LA volume and LA volume index.[75] Further, observational studies by Gurses et al.[76] also found that serum galectin-3 and LA volume index were significantly greater in patients with AF, which indicated that galectin-3 levels in AF maybe correlated with AF-induced atrial remodeling.[76] They also found that serum galectin-3 levels were also significantly higher in patients with persistent AF than those with paroxysmal AF.[76] The newest study by Yalcin et al.[77] tested 33 patients with paroxysmal AF who underwent delayed enhancement MRI (DE-MRI) before cryoballoon-based AF ablation.[77] LA volume index and serum galectin-3 levels were found to be independently correlated with extent of LA fibrosis detected with DE-MRI in paroxysmal AF patients with preserved LV function.[77] This finding indicated that serum galectin-3 levels are significantly related to atrial remodeling in paroxysmal AF patients with preserved LV function.

Current evidence demonstrates the potential value of galectin-3 as a prognostic marker in AF. Ho et al.[78] examined the possible association of circulating galectin-three concentrations and the AF incident. They measured serum galectin-3 concentrations in 3306 participants from a large, well-characterized, community-based sample.[78] Over a median follow-up period of 10 years, 250 participants developed incident AF. The results showed that higher circulating galectin-3 concentrations were associated with higher risks of developing AF. Another study by Kornej et al.[79] assessed the impact of AF catheter ablation on galectin-3 and evaluated its prognostic impact for predicting rhythm outcome after catheter ablation. They found that galectin-3 levels were higher in AF patients compared with AF-free controls.[79] Moreover, higher galectin-3 levels were associated with female gender, higher BMI and both CHADS2 and CHA2DS2-VASC scores,[79] however, only BMI was significantly associated with galctin-3 on a multivariable analysis. It seems like galectin-3 levels are higher in AF patients, which is driven by cardiometabolic risks but not the heart rhythm.[79]

The precise mechanisms of atrial remodeling remain unclear; however, the present studies have taken the first step in elucidating the mechanisms involving galecitin-3. Galectin-3, as a novel fibrosis and inflammation biomarker, can potentially be involved in the pathophysiologic mechanisms and related-signaling pathways of AF-induced atrial remodeling.

  Conclusion Top

Although the initial studies demonstrating the role of galectin-3 in inflammation and fibrosis were reported more than a decade ago, in recent years, galectin-3 as a new circulatory biomarker has been widely studied for its role in myocardial inflammation and cardiac remodeling. With an increasing number of studies focusing on the role of galectin-3 in cardiovascular diseases, the significance of galectin in this field has been clearly established.

Many clinical and experimental studies used a large body of data or different models to analyze the significance of galectin-3 on various aspects of myocardial fibrosis and cardiac remodeling. According to the previous experimental and epidemiological evidence, it seems reasonable that galectin-3 may be regarded as a promising tool to evaluate risk stratification and outcome prediction of cardiovascular diseases. Although galectin-3 is upregulated in cardiac remodeling of various cardiovascular diseases, current studies have not proved that galectin-3 is a better predictor for prognosis of cardiac remodeling than NT-proBNP, BNP, sST2, or GDF-15. However, galectin-3 levels, together with other biomarkers may offer a better and more specific assessment in outcomes of patients in all-cause of cardiovascular diseases. In addition, studies have found perturbation of galectin-3 function, either by blocking its expression with siRNA or by pharmacologically inhibiting its activity with external carbohydrate ligands, produced encouraging results in several preclinical models. The mechanistic details of the anti-fibrosis activity of galectin-3 in all sorts of cardiovascular diseases are not completely understood and more studies should focus on the pathophysiologic process and signaling pathways of how galectin-3 could cause or aggravate cardiac remodeling.

In summary, we suggest a causal role of galectin-3 in the development of cardiac remodeling, and we argue that serum galectin-3 levels could potentially become a new risk predictor for adverse cardiovascular events. Galectin-3, as a novel marker and therapeutic target, deserves further scientific attention in the cardiovascular field. After precise mechanisms of galectin-3 in cardiac remodeling have been clarified, galectin-3–targeted therapy may potentially be an available option to ameliorate or even reverse the progression of cardiac remodeling in cardiovascular diseases.

Financial support and sponsorship

This study was financially supported by the National Natural Science Foundation of China (81570050) and Innovation Project Foundation of Central South University (2016zzts530).

Conflicts of interest

There are no conflicts of interest.

  References Top

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