Galectin-3 Mediated Cardiovascular Fibrogenesis: An Important

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Chapter 24

Galectin-3 Mediated Cardiovascular Fibrogenesis: An Important Cause of Heart Failure and Cardiovascular Mortality Wouter C. Meijers and Rudolf A. de Boer* University Medical Center Groningen, Department of Cardiology, Groningen, The Netherlands *E-mail: [email protected]

Cardiac remodeling is the heart’s primary adaptive response to injury. Remodeling is characterized by myocyte hypertrophy, but fibrosis formation in the interstitial space is also dominant. It has been established that galectin-3 plays an important role in tissue inflammation, immunity, and fibrosis. Galectin-3 is highly upregulated in adverse cardiac remodeling and heart failure (HF). Several lines of evidence suggest that galectin-3 is not only a marker (bystander) in cardiac remodeling but it may actively contribute as well. First, plasma galectin-3 is increased in human subjects prone to develop HF, and in patients with established HF galectin-3 has emerged as a useful biomarker reflecting the severity of HF. Second, galectin-3 has been shown to contribute to the formation of fibrosis (fibrogenesis) – administering exogenous galectin-3 leads to cardiac fibrosis. Reversely, disruption of galectin-3 is associated with the absence of cardiac fibrosis. The effects of galectin-3 on fibrosis have also been established in other organs, for instance kidney and liver. Since complete (genetic) disruption is not clinically feasible, pharmacological inhibition of galectin-3 is an attractive therapeutic modality to inhibit cardiac remodeling and HF development. Various food products, containing oligosaccharides such as pectins, may act as neutralizing ligands or inhibitors for galectin-3. Pectins can bind to galectin-3’s carbohydrate recognition domain (CRD)

© 2012 American Chemical Society In Galectins and Disease Implications for Targeted Therapeutics; Klyosov, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


and have been shown to inhibit carcinogenesis and other galectin-3-driven diseases. Recently, it has been reported that cardiac remodeling, fibrogenesis and HF development may also be amenable to inhibition of galectin-3. Circumstantial evidence for a potential role of galectin-3 comes from the observation that consumption of dietary fibers, e.g. from cereals and fruits, that are rich in pectins, has consistently been associated with a lower risk for heart disease. The search for the precise mechanism of galectin-3 in HF and better treatment aimed against galectin-3 is ongoing. Candidate anti-galectin-3 treatments will first have to be tested in animal models, and should then be further evaluated in clinical trials.

Heart Failure Heart failure (HF) is a clinical syndrome with primary symptoms including shortness of breath and fatigue, signs including fluid retention, ánd objective evidence of abnormal structure or function of the heart. The prevalence of HF in the western world is about 1-2% (1) and when ≥ 75 years it is 8.4% (2). The life time risk for subjects from the general population to develop HF after the age of 55 is 30% (3). Despite optional conventional treatment (4) survival remains low with a medium mortality of more than 50% after 5 years (3). Main causes of HF are hypertension, myocardial infarction due to ischemic heart disease and cardiomyopathies.

Cardiac Remodeling and Fibrosis The heart’s general response to injury is an adaptive response that is referred to as cardiac remodeling. Hallmark events of cardiac remodeling include myocyte hypertrophy, loss of cardiomyocytes (apoptosis, necrosis), and changes in the interstitial space, predominantly fibrosis (5). Recently, the interest in pathways of cardiac remodeling is rising. The cardiac interstitium consists of fibroblasts, blood vessels, lymphatic vessels, adrenergic nerve endings and extra cellular matrix (ECM). The ECM comprises several proteins including collagens, fibronectin, proteoglycans and laminin, but also different proteases and growth factors, produced by cardiac fibroblasts differentiating into myofibroblasts. Besides ECM protein production, cardiac fibroblasts also facilitate mechanical, electrical and chemical signaling in the heart and influence the development and remodeling of myocardial vasculature (6, 7). The function of ECM is to provide a structural network for transmitting force, generated by individual myocytes into organized systolic contraction of the heart. Furthermore, it contributes to passive stiffness in diastole and prevents overstretch, myocyte slippage, and tissue deformation during ventricular filling (8). As such, ECM remodeling is an essential process in cardiac remodeling (9). 398 In Galectins and Disease Implications for Targeted Therapeutics; Klyosov, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.

Galectin-3


Galectin-3 is a 29-35 kDa chimaera-type galectin, which is unique because of its extended N-terminal domain linked to a single C-terminal carbohydrate-recognition domain. The galectin family consists of 3 different structures (Figure 1).

Figure 1. Galectin family and their structures. The gene that encodes galectin-3, LGALS3, is a single gene located on chromosome 14, locus q21–q22 (10). Galectin-3 belongs to a family of soluble β-galactoside-binding lectins that play regulatory roles in inflammation, immunity, fibrosis, and cancer (11). Regulation of galectin-3 has not extensively been studied – most consistently galectins have been overexpressed in cancerous cells (12).

Galectin-3 and Heart Failure In 2004, it was observed that galectin-3 is the most over-expressed gene in failing hearts from transgenic hypertensive rats, found in a microarray study (13). Galectin-3 is secreted by hitherto unexplained mechanisms. An FDA-approved ELISA has been developed and allows for reliable quantitation of galectin-3 in plasma or serum. It has convincingly been shown by many groups that plasma galectin-3 levels are increased in HF, and that plasma galectin-3 levels provide strong prognostic value, independent from established predictors like age, gender and kidney function (14). In line with the experimental observations (vide infra) that galectin-3 is co-localized with fibrosis, it has also been observed that galectin-3 levels relate to markers of matrix turnover (11).

Galectin-3: Emerging Role in Adverse Cardiac Remodeling and Heart Failure It has been described that galectin-3 interacts with a wide array of glycoproteins that are also located in het ECM in the heart, including laminin, collagen, synexin and integrins (15). Especially pertinent to increased galectin-3 regulation and secretion is macrophage migration. Influx of macrophages has 399 In Galectins and Disease Implications for Targeted Therapeutics; Klyosov, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


been described in many forms of cardiac injury, including infarction, myocarditis, and also chronic LV remodeling (16, 17). The chronic inflammatory state of the HF patient is supported by increased levels of CRP and high total leukocyte counts, especially in patients with increased galectin-3 (18). The seminal paper from Sharma and colleagues first described galectin-3 in HF (15). Galectin-3 was upregulated in the left ventricular tissue of Ren2- rats, in parallel to various other ECM proteins, such as collagens, oestoactivin, fibronectin and others, supporting the paramount role galectin-3 plays in ECM homeostasis and integrity. During the compensated phase of cardiac remodeling, myocardial galectin-3 expression was increased to higher levels in rats that later progressed towards overt HF compared with rats that remained compensated. So, besides an interesting correlation, this suggested that galectin-3 would actively contribute to the progression of cardiac remodeling and HF. Further experiments showed that continuous infusion of galectin-3 for four weeks into the pericardial sac induced cardiac remodeling, myocardial fibrosis and cardiac dysfunction, with depressed LV ejection fraction, fractional shortening, and increased lung weight-to-body weight ratio compared with rats receiving placebo infusion. They also found an increase in collagen volume, especially collagen type I (13). Galectin-3 colocalized to sites of extracellular matrix, fibrosis, and accumulation of ECM proteins. The observation that galectin-3 causes myocardial fibrosis and LV dysfunction has been confirmed by others (23). Furthermore, independent corroborating evidence for the pivotal role of galectin-3 in tissue fibrosis was obtained studying mice deficient for the gene encoding galectin-3 (Gal3 KO mice). In a mouse model of liver fibrosis, mice with complete genetic disruption of galectin-3 had less severe fibrosis of their livers upon injection of a pro-fibrotic compound (19). In a subsequent study from the same group, it was shown that Gal3KO mice are also protected from renal fibrosis (20). In a model of unilateral uninephrectomy, Gal3KO mice showed reduced collagen deposition, less macrophage influx, although expression levels of TGF-β and Smad 2/3 phosphorylation were comparable. Collectively, these observations clearly indicated that Galectin-3 is produced in adverse cardiac remodeling and HF, might contribute to the pathophysiology, but it remains to be resolved if targeted inhibition of galectin-3 might represent a viable target in HF treatment.

Galectin-3: Emerging Role as a Biomarker in Heart Failure Extensive cardiac remodeling is the most important determinant of disease progression and highly correlated with poor prognosis. It is of utmost importance to recognize these patients who are at the highest risk for adverse outcome, as this allows more aggressive interventions. Circulating galectin-3 levels are an independent predictor of mortality in patients with chronic HF (14, 21). Patients with chronic HF and (NYHA III/IV) with high baseline galectin-3 had worse survival independent from NT-proBNP (14). Furthermore, the prognostic importance of plasma galectin-3 levels appears to be stronger in patients with HF with preserved ejection fraction (HFPEF) (21). Additionally, patients who 400 In Galectins and Disease Implications for Targeted Therapeutics; Klyosov, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


suffered a myocardial infarction were more prone to develop HF when their baseline galectin-3 baseline levels were increased (22). In more advanced HF, the role of galectin-3 needs further study. A recent study in patients receiving cardiac resynchronization therapy (CRT) indicated that galectin/3 did not predict response to CRT (23). Patients with HF who are waiting for heart transplantation (Htx) can be supported by a mechanical support device or treated with total artificial hearts (TAH) when necessary Patients who had high levels of galectin-3 before TAH implantation showed no significantly changes in galectin-3 levels 30 days after the TAH implantation. This observation suggests extracardiac production of galectin-3 in patients with end-stage HF. Higher galectin-3 levels did however still predict adverse outcome of this bridging therapy (24). Besides HF, plasma galectin-3 levels predict all-cause mortality in the general population (25). There is evidence that highlight the importance of heart-kidney interactions in HF (23), but data in patients with renal disease are currently lacking. Galectin-3 is associated with kidney fibrosis in animal studies (20), suggesting that galectin-3 is upregulated in a cardio-renal profibrotic pathway (23). In patients with acute decompensated HF who have high levels of galectin-3, there is an association between high age, poor renal function, higher CRP and higher NTproBNP (26).

Inhibition of Galectin-3 by Pectins Galectin-3 may be bound by ligands, mainly carbohydrates that specifically bind to galectin-3’s CRD. The CRD of galectin-3 acts as an unique on-off switch. It has been demonstrated that neutral sugar side chains, containing terminal galactose at the nonreducing end of the polysaccharide chain, bind galectin-3. The binding between the complexes seems to be a lectin-carbohydrate interaction because of the force needed to rupture the binding (27). Natural occurring ligands in the heart for galectin-3 are various matrix proteins and oligosaccharides. Recently, it has been acknowledged that several oligosaccharides present in various foods are also ligands to galectin-3. Pectins are typical examples of such oligosaccharides – pectins are present in fruit peels, okra, sugar beets and many more natural foods. It is believed that pectins bind to galectin-3 and render it unavailable to the endogenous ligands, thus acting as neutralizing ligands. Pectin-derived bioactive fragments bind to galectin-3’s CRD with various affinity; this is subject to investigation as a pectin with strong affinity might afford protective effects in galectin-3 related disease. The potential efficacy of pectins to reduce galectin-3 bioactivity has been proven in non-cardiac disease only. Modified citrus pectin (MCP) is the best studied pectin in this perspective. MCP is a dietary fiber that is soluble in water which is found in the peel and pulp of citrus fruits and modified by high pH and temperature (28, 29). Since galectin-3 plays an important role in cancer and metastasis development, MCP has been studied for its efficacy in preventing carcinogenesis. Fitting this hypothesis, MCP seems to be a therapeutic option in experimental and clinical colon and metastatic prostate cancer (30, 31). The therapeutic pathway 401 In Galectins and Disease Implications for Targeted Therapeutics; Klyosov, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.

in controlling cancer is indeed due to blockage of galectin-3. Mice with injected melanoma cells were started on MPC treatment and showed decrease of lung colonization (32). MCP has shown to interfere with cell-cell interactions mediated by cell surface carbohydrate-binding galectin-3 molecules (31). Furthermore, in a model of unilateral ureter obstruction, MCP was shown to reduce renal fibrosis (28).


Inhibition of Galectin-3 in HF The concept to inhibit galectin-3-related myocardial fibrogenesis and LV dysfunction has been explored first by Liu and colleagues (23).They tested N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), a tetrapeptide with established anti-inflammatory and antifibrotic capacities. The potentially protective effects of Ac-SDKP have been demonstrated in HF models of hypertension and post-myocardial infarction (33, 34). Ac-SDKP has inhibitory effects on the very mechanisms that are governed by galectin-3 namely, myocardial inflammation (macrophages influx), and myocardial fibrogenesis, including collagen synthesis, TGF-β1 expression, and SMAD3 phosphorylation. The authors concluded that Ac-SDKP prevented galectin-3-mediated myocardial damage via the TGF-β/SMAD3 signaling pathway (Figure 2) (35).

Figure 2. Common signaling pathways that contribute to myocardial fibrosis. (see color insert) Our group has recently conducted a series of experiments to establish if galectin-3 disruption or inhibition could attenuate progressive adverse cardiac remodeling. We have studied Gal3 KO mice, and subjected the mice to two established perturbations causing LV remodeling: infusion of Angiotensin II (AngII) and transverse aortic constriction (TAC). Both perturbations led in wild type (WT) mice to progressive remodeling, characterized by LV hypertrophy, fibrosis, and associated functional abnormalities, most prominently increased LV end-diastolic pressure and impaired LV relaxation. Gal3 KO mice undergoing 402 In Galectins and Disease Implications for Targeted Therapeutics; Klyosov, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


the same perturbations, showed identical severity of LV hypertrophy, however, myocardial fibrosis was far less prominent, and mice had less severe diastolic dysfunction (26). Pharmacological inhibition of Galectin-3 was tested in a rat model of spontaneous cardiac remodeling. The galectin-3 inhibitor N-acetyl-DLactosamine (N-Lac) was administered to Ren-2 rats for six weeks. Ren-2 rats treated with N-Lac were protected from adverse cardiac remodeling, as indicated by better survival, better cardiac function, and less fibrosis. The improvement was associated with favorable genetic program (lower expression of genes associated with collagen synthesis and processing (36) (Figure 3).

Figure 3. Fibrosis and Fractional Shortening in Ren-2 Rats (control vs. Galectin-3 inhibitor). (see color insert)

Inhibition of Galectin-3 in Heart Failure: Clinical Clues There are no data available if galectin-3 inhibition could benefit humans suffering from HF. However, there is some circumstantial evidence to suggest this may be true. First, consumption of dietary fibers, e.g. from cereals and fruits, has consistently been associated with a lower risk for coronary artery disease (37). Such dietary fibers may act as galectin-3 inhibitors, although this has not formally been studied. It has been observed that diets that contain soluble fiber-rich whole grains are associated with improvement of blood-pressure control among patients treated with anti-hypertensive medication, a significant reduction in the number of anti-hypertensive medication, and improvement in serum lipids and plasma glucose. Taken these three factors into account this diet can be very effective in a reduction of cardiovascular disease risk (Table 1) (38). Interestingly, the intake of whole grain breakfast cereals is also associated with a lower risk of HF (39).

403 In Galectins and Disease Implications for Targeted Therapeutics; Klyosov, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.

Table 1. Dietary fiber intake related to relative risk for disease based on estimates from prospective cohort studies*


Disease

Number of patients

Included studies

Relative risk** (95% CI)

Coronary heart disease

158.327

7

0.71 (0.47-0.95)

Stroke

134.787

4

0.74 (0.63-0.86)

Diabetes

239.485

5

0.81 (0.70-0.93)

Obesity

115.789

4

0.70 (0.62-0.78)

*

Table adapted from Anderson, J.W., et al. Health benefits of dietary fiber. Nutr. Rev. 2009, 67 (4), 188-205. ** Relative risks adjusted for demographic, dietary and non-dietary factors.

Future Perspectives There is accumulating evidence that galectin-3 is important for HF development and progression. Furthermore, galectin-3 is an attractive and feasible target for therapy. What will be needed before galectin-3 inhibition becomes mainstay therapy in HF? First, we need to further dissect what precise role galectin-3 plays in the pathophysiology of HF. Second, we need to study what inhibitors may be used, study if certain types of inhibitors confer superior efficacy, and ideally, identify what sequences are involved. This will require intense interaction between biochemists, chemical, nutritional and pharmaceutical industry and academic researchers. These studies likely will be complex, given the different roles galectin-3 serves in various diseases, both cardiac and non-cardiac. Finally, we need to design elegant animal studies that proof efficacy and safety parameters. Ultimately, clinical trials should be conducted to evaluate the effect of these inhibitors, which might improve survival of patients suffering from this devastating disease. Conflicts of Interest BG Medicine (Waltham, MA, USA) holds certain rights with respect to the use of galectin-3 in HF. The UMCG, that employs Dr. de Boer, has received research grants from BG Medicine. Dr. de Boer received consultancy fees from BG Medicine.

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Galectin-3 Mediated Cardiovascular Fibrogenesis: An Important

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