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Involvement of galectin-3 in cadmium-induced cardiac toxicity/Galektin-3'un kadmiyuma bagli kardiyotoksisiteye katilimi.

ABSTRACT

Objective: Accumulation of the wide spread environmental toxin cadmium (Cd) in tissues results in toxicity. Heart is one of the most effected tissues. Cd exposure induces inflammation in effected tissues. The present study was focused to evaluate roles of tumor necrosis factor alpha (TNF-[alpha]) and interleukin-6 (IL-6) in Cd toxicity and their relationships with galectin-3 levels.

Methods: In this experimental study, male Wistar rats were divided randomly to control and experimental groups. Experimental group was exposed to Cd at the dose of 15 ppm for 8 weeks (n=10/group). Inflammatory status in hearts was evaluated with measurement of tissue TNF-[alpha] and IL-6 levels. Histopathological examination of heart was carried out by light microscopy. Heart tissue caspase-3 level was used to identify apoptosis. Tissue galectin-3 level was evaluated by ELISA. Statistical difference between groups was evaluated by unpaired Student t-test, correlation was analyzed by Pearson's test.

Results: Heart sizes were increased after Cd toxicity. A significant increase in galectin-3 tissue levels was seen after Cd toxicity, this was accompanied with a significant increase in the TNF-[alpha] (control: 402[+ or -]39, Cd: 793[+ or -]26 pg/g tissue, p<0.001) and IL-6 (control: 150[+ or -]78, Cd: 325[+ or -]65 pg/g tissue, p<0.001) levels. Histopathological examination under light microscope suggested a combination of ongoing necrosis and apoptosis. Increased caspase-3 levels were measured after Cd toxicity (control: 12[+ or -]2, Cd: 18[+ or -]3 pmol/[micro]g/min, p<0.001).

Conclusion: Chronic Cd administration induces inflammation and apoptosis in rat hearts. Cadmium causes increased galectin-3 production from heart tissue. The formation of TNF-[alpha] due to Cd exposure may likely trigger this mechanism. (Anadolu Kardiyol Derg 2011; 11: 479-84)

Key words: Cadmium, heart, galectin-3, caspase-3, tumor necrosis factor alpha, interleukin-6

OZET

Amac: Cevresel toksinlerden biri olan kadmiyumun dokularda birikimi ciddi toksiteye neden olur. Kalp en sik etkilenen organlardan biridir. Kadmiyuma maruz kalma dokularda enflamasyonla sonuglanir. Bu calismada kadmiyum toksitesinin kardiyak dokuda proenflamatuvar sitokinlerden tumor nekrozis faktbr-alfa (TNF-[alpha]) ve interlbkin-6 (IL-6) duzeylerine etkisi ve doku galektin-3 duzey degisjminin belirlenmesi hedeflenmistir.

Yontemler: Bu deneysel galismada, erkek Wistar siganlar randomize kontrol ve deney grubuna ayrilmis, deney grubu 8 hafta, gunluk 15 ppm kadmiyuma maruz birakilmistir (n=10/grup). Kalp dokusunda enflamasyon doku TNF-[alpha] ve IL-6 duzeyleri ile belirlenmistir. Kardiyak doku histolo-jik olarak incelenmistir. Dokuda apoptozis caspase-3 duzeyleri ile belirlenmistir. Galektin-3 duzeyi ELISA ile olgulmustur. Gruplar arasi farklar t-testi, korelasyon Pearson's testi ile degerlendirilmistir.

Bulgular: Kadmiyum uygulanan grupta makroskopik olarak kardiyomegali gozlenmistir. Dokuda TNF-[alpha] (kontrol: 402[+ or -]39, Cd: 793[+ or -]26 pg/g doku, p<0.001), IL-6 (kontrol: 150[+ or -]78, Cd: 325[+ or -]65 pg/g doku, p<0.001) ve galektin-3 duzeyleri belirgin artmistir. Histopatolojik incelemede kadmiyum kalp dokusunda belirgin nekroz ve apoptoza neden oldugu gozlenmistir. Doku kaspaz-3 duzeyleri artmistir (kontrol: 12[+ or -]2, Cd: 18[+ or -]3 pmol/pg/dk, p<0.001). Sonuc: Kadmiyum toksitesi kalp dokusunda enflamasyona, apoptoza neden olmaktadir. Kadmiyum kardiyak dokuda galektin-3 duzeyini arttir-maktadir. Dokudaki enflamasyonun artmasi galektin-3 duzeyinin artisina neden olan mekanizmalardan biri olabilir. fAnadolu Kardiyol Derg 2011; 11:479-84)

Anahtar kelimeler: Kadmiyum, kalp, galektin-3, caspase-3, tumor nekrozis faktor--alfa, interlokin6

Introduction

Cadmium (Cd) exposure occurs widely In general population, especially low-level chronic exposure through smoking and dietary sources, but it is known also as one of most toxic environmental and industrial pollutants. Cadmium accumulates in the body because of slow excretion. Cd causes toxicity in different organs, heart is one of the most effected tissues and oxidative damage usually occurs after Cd toxicity (1-4). Many mechanisms are defined to explain pathophysiology of the Cd toxicity; inflammation is one of them (5).

Galectins are a large family of animal lectins that contain carbohydrate-recognition domains consisting of amino acids that are responsible for carbohydrate binding (6). Galectins can behave as a pro-inflammatory or anti-inflammatory mediator by modulating the physiology and responses of immune cells, including macrophages, T and B cells, neutrophils, eosinophils and mast cells (7). Galectin-3 has also antiapoptotic effect and tumor associated immune and inflammatory responses (8). It was shown that galectin-3 also takes part in the mechanism of the ischemia-induced damages (9), it behaves as an inflammatory substance. Latest studies focused on the involvement of galectin-3 in cardiac failure, cardiac remodeling and in the fibrotic process (10). Galectin-3 is accepted as a novel biomarker in cardiac failure progress (11). Recent studies showed that environmental cadmium exposure is associated with cardiovascular disease, significantly increased stroke and heart failure prevalence (12).

Role of galectin-3 during Cd toxicity has not been reported yet. Additionally, its relationship with tumor necrosis factor alpha (TNF-[alpha])is still unclear. This study was designed to evaluate role of galectin-3 in the cardiac toxicity of Cd and whether their levels correlated with inflammatory markers such as TNF-[alpha] level and interleukin-6 (IL-6).

Methods

Study animals

Twenty adult male Wistar rats (150-200 g) were used for toxicity model. Rats were divided randomly control and Cd toxicity groups (n=10). Animals were housed at Ankara University Animal Laboratory under controlled light (12L: 12D) and temperature with free access to food and water. All aspects of animal handling and surgery were conducted in accordance with appropriate animal experiments criteria established by Helsinki Declaration by the permission of Ankara University, Faculty of Medicine, Ethical Committee.

Experimental design

The rats were given 15 ppm of Cd in their drinking water (cadmium chloride dissolved in distilled water) for 8 weeks. Cd-chloride (Cd[Cl.sub.2], anhydrous) was obtained from Sigma (St. Louis, MO, USA). At the end of 8 weeks the rats were sacrificed under anesthesia, and their hearts were taken out for further evaluations. Half of the hearts were used for determination of Cd concentrations; the other half was used for measurements of protein levels. All tissue samples were stored at -80[degrees]C until they were used for evaluation.

Histological examination

Following the removal of hearts, they weighted and sizes of left and right ventricular wall thickness and atrioventricular opening diameters of them were measured and recorded. After fixation in 10% buffered formalin, tissue samples were dehydrated and embedded in paraffin, cut at about 5 pm thick and stained with hematoxylin-eosin. Samples were evaluated under light microscope (Olympus, Japan)with X50-100 magnification.

Biochemical determinations

Protein extracts were prepared from fresh tissue samples in Brij 150 lysis solution which contains a cocktail of protease inhibitors aprotinin (2 [micro]g/ml), leupeptine (2 [micro]g/ml), pepstatine (2 [micro]g/ml), PMSF (2 pg/ml). Chemicals were obtained from Sigma unless otherwise stated. Lysis solution was added as two folds of tissue weight by volume and homogenized (Powergen 125, Fisher, PA, USA).

Measurement of cytokine levels

Tissue supernatants were harvested and analyzed for TNF-[alpha], interleukin-6 (IL-6) and galectin-3 in triplicate using an ELISA kit (Cytolab/PeproTech, Israel). The lower detection limits of the assay were 16 pg/ml for TNF-[alpha], 30 pg/ml for IL-6 and 200 pg/ml for galectin-3.

Tissue cadmium levels

Half of the hearts were used for determination of the Cd concentration by flame-less atomic absorption spectrophotometry (AAS). All reagents and chemicals were of analytical grade or higher purity. Trace pure nitric acid (HN[O.sub.3]; Merck, NJ, USA) as well as Cd standard solutions assigned for atomic absorption spectrometry (Sigma, Mo, USA) were used in metals analysis. The weighed heart tissue slices were dry mineralized at 450[degrees]C in an electric oven. After ashing, the samples were dissolved in 10 ml of 1 M HN[O.sub.3]. Cadmium was determined by flameless AAS method with electro thermal atomization in a graphite cuvette.

Caspase-3 levels

Protein content of homogenates was determined with Bradford method. Then 100 [micro]g of proteins were diluted with assay buffer (50 mM HEPES, pH 7.4, 100 mM NaCI, 0.1% CHAPS, 10 mM DTT, 2 mM EDTA, 2 mM EBTA, Triton X-100, 0.1%) and incubated at 25[degrees]C with the colorimetric substrates (Sigma, Mo, USA): Ac-DEVD-pNA. Final concentration was 200 [micro]M for all substrates in 96-well microtiter plates. Cleavage of the p-nitroaniline (pNA) dye from the peptide substrate was determined by the measurement of absorbance of pNA at 405 nm in a micro plate reader. Results were calibrated with known concentrations of p-NA and expressed in picomole substrate cleaved/minute and per microgram protein at 25[degrees]C.

Statistical analysis

Statistical analyses were performed using SPSS version 10.0 software for Windows (SPSS Inc, Chicago, II, USA). Data were evaluated first for homogeneity of variance with Shapiro-Wilk test. Student's t-test (unpaired) was used for comparison of continuous variables between control and cadmium exposure groups. Correlations between galectin-3 and cardiac measurements and TNF-[alpha] level within the same tissues were evaluated with Pearson's test. Results were expressed as mean[+ or -]SD, p<0.05 was accepted as statistically significant.

Results

After 8 weeks Cd exposure no mortality occurred. Cd concentrations of the heart tissue control and cadmium toxicity groups were 2.28[+ or -]0.26; 52.77[+ or -]1.95 ng/g tissue (mean[+ or -]SD), respectively.

Histological examination

Hearts were evaluated under light microscope. Heart sizes increased after Cd toxicity. Ventricular wall thickness and atrio-ventricular opening diameters increased significantly in Cd toxicity group (Table 1). Heart size (r=0.834, p<0.01) and right ventricular thickness (r=0.944, p<0.001) were found to be significantly correlated with tissue galectin-3 levels in rat hearts. Hearts of the Cd group are hypertrophied (Fig. 1). Myocardium was in normal aspect in control group (Fig. 2.1). Some degenerative differences were observed in cadmium treated group such as congestion in the vessels (Fig. 2.2), nuclear lysis, vacuolization of cytoplasm and irregularity (Fig. 2.3) of myofibrils (Fig. 2.4).

Biochemical evaluations

As seen in the Fig. 3-5 our results showed that chronic cadmium administration in rats caused marked increases in the caspase-3, TNF-[alpha], IL-6 and galectin-3* levels (p<0.001, p<0.05*, Table 2). Tissue levels of TNF-[alpha], galectin-3 were strongly correlated with each other (r=0.872, p<0.0001).

Discussion

In this study, we aimed to evaluate roles of proinflammatory cytokines TNF-[alpha], IL-6 and galectin-3 during 8 weeks of Cd toxicity. Oral Cd administration in rats results in increased TNF-[alpha], IL-6 production in heart tissue in correlation with increased galectin-3 levels. Our results showed that Cd induces caspase activated apoptosis, causes degenerative changes in rat hearts. It is known that Cd exposure causes severe damage in different organs of the body. Heart is one of them. We found degenerative changes during histopathological evaluation of the hearts in Cd group. Cadmium induced apoptosis in cardiomyocytes. It was supported by increased caspase-3 levels in Cd group.

[FIGURE 1 OMITTED]

Several immunological and non-immunological mechanisms of Cd toxicity have been proposed. Pathological proinflammatory and pro-apoptotic stimuli, like TNF-[alpha] can cause activation of caspase cascades and apoptosis by direct or indirect processing of caspase-3. Tumor necrosis factor-[alpha] and IL-6 levels increased and correlated with caspase-3 levels in Cd group. The cardiotoxicity of the Cd seems as it was mediated by inflammation. Although conflicting results were found related to immunomodulatory actions of Cd (13-15), its effect is seemed to be dose and time dependent. It was found that high doses of Cd suppress immune response where as with lower doses immune stimulatory effects become more prominent. A growing body of evidence links macrophage activation and fibrosis to the pathogenesis of heart failure. Studies are increasing that link macrophage activation and fibrosis to the pathogenesis of heart failure. Accordingly, there has been increasing interest in developing therapeutic agents with anticytokine properties in patients with heart failure (16).

[FIGURE 2 OMITTED]

A role for galectin-3 in the pathophysiology of heart failure has been reported recently. Galectin-3 could induce primary immune response and cytokine production and has important roles in metastasis, migration, inflammation, fibrosis, and in the main mechanisms take part in pathogenesis and progress of heart failure (6, 7, 10). Galectin-3 is chemo-attractant for leukocytes. It is important for modulation of integrins and metalloproteinases (6, 7). Deficiencies in accumulation of inflammatory cells, decreased response to peritonitis, lower levels of NF-[kappa]B response and decreased inflammatory cell survival were seen in galectin-3 deficient mice (17). Increased myocardial galectin-3 expression is seen during progression to heart failure. The up-regulation of myocardial galectin-3 has been demonstrated in a rat model of heart failure prone hypertensive hearts (18), interferon [gamma]-induced murine chronic active myocarditis and cardiomyopathy together with TNF-[alpha], IL-12 and the macrophage-attracting chemokines MCP1 and MIPI-[alpha] (19).

Cardiac remodeling is an important determinant of the clinical outcome of heart failure, as it is linked to disease progression and poor prognosis. Increased inflammation and fibrosis are main determinants of ventricular remodeling. Resent findings support the involvement of galectin-3 in cardiac remodeling and in the fibrotic process and, as suggested by two recent experimental studies of liver and kidney fibrosis (20, 21). There is evidence that inflammation contributes to end organ damage. It has shown that N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) prevents inflammation, cell proliferation and fibrosis in the heart and kidney in a AN6 II-induced hypertension model. They found that galectin-3 expression increased in left ventricular remodeling together with inflammatory markers IL-6, transforming growth factor-[beta] (TGF-[beta]), and TNF-[alpha] (22). Liu et al. (23) recently showed that the co-infusion of Ac-SDKP with galectin-3 into the pericardial sac, inhibited fibrosis and inflammation and decreased cardiac dysfunction.

Together, the experimental data underlying the potentially important role that galectin-3 may play in cardiac remodeling, and interference with galectin-3 levels seems to effectively reverse cardiac remodeling. Galectin-3 over expression causes changes in the expression levels of cell cycle regulators, including cyclin D1, which is important for myocardial fibrosis and heart failure. Nuclear galectin-3 expression is associated with cell proliferation, and this effect is mediated through enhanced cyclin D1 promoter activity (24). Galectin-3 has ability to bind to cardiac fibroblasts and it induces fibroblast proliferation via the activation of cyclin D1. The exact myocardial localization of galectin-3 has not been known exactly. However, immunohistochemistry and confocal microscopy analyses of hypertrophied rat myocardium showed that galectin-3 binding sites were localized predominantly to the myocardial matrix, in macrophages and fibroblasts. Galectin-3 is necessary for normal phagocytic activity. In hypertrophied hearts and during active myocarditis, significant infiltrations of activated macrophages were observed and galectin-3 was found to be co-localized with macrophages (18).

[FIGURE 3 OMITTED]

[FIGURE 4 OMITTED]

[FIGURE 5 OMITTED]

Heart sizes and ventricular hypertrophy were found significantly correlated with tissue galectin-3 levels in rat hearts, and there was strong correlation between tissue TNF-[alpha] and galectin-3 levels. Taken together, with from available clinical data, plasma and/or serum galectin-3 is increased in acute and chronic heart failure and previous animal studies our results support the idea of the involvement of galectin-3 in cardiac remodeling and inflammation. Galectin-3 might be of particular value to predict prognosis and as a novel biomarker in cardiac pathologies even in toxicities.

Study limitations

The functional analysis of heart, in case of ventricles and valves was not evaluated in this study. Echocardiographic analysis might give more information about Cd induced damage in rat hearts.

Conclusion

Our results support the concept of considering galectin-3 as a new target for therapeutic intervention and prognostic biomarker in different heart dysfunction and pathologies. Further studies will explain the pathophysiological mechanisms of the involvement of galectin-3 in Cd induced toxicity in heart.

Conflict of interest: None declared.

doi:10.5152/akd.2011.130

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Nuray Yazihan, Mehtap Kacar Kocak, Ethem Akcil, Onur Erdem [1], Ahmet Sayal [1], Cengiz Guven*, Nalan Akyurek [2]

From Departments of Pathophysiology and * Histology, Faculty of Medicine, Ankara University, Ankara

[1] Department of Pharmaceutical Toxicology, Gulhane Military Medical Academy, Ankara

[2] Department of Pathology, Faculty of Medicine, Gazi University, Ankara-Turkey

Address for Correspondence/Yazisma Adresi: Dr. Nuray Yazihan, Department of Pathophysiology, Faculty of Medicine, Ankara University, Sihhiye, 06100, Ankara-Turkey Phone: +90 31231030 10/372 E-mail: nurayyazihan@yahoo.com

The study was presented at the 4th International Symposium on Trace Elements and Minerals in Medicine and Biology, FESTEM; 9-12 June, 2010, St Petersburg, Russia Accepted Date/Kabul Tarihi: 31.03.2011 Available Online Date/Cevrimici Yayin Tarihi: 25.07.2011
Table 1. Cardiac sizes of control and cadmium--induced toxicity
groups

Variables                 Control group      Cadmium group        p

Heart weights, gr        1.04[+ or -]0.10   1.66[+ or -]0.06   <0.0001

Left ventricular          3.8[+ or -]0.5     4.0[+ or -]0.6     >0.05
wall thickness, mm

Right ventricular         2.3[+ or -]0.5     1.3[+ or -]0.2     0.004
wall thickness, mm

Left atrioventricular    1.02[+ or -]0.09   1.2[+ or -]0.13     0.028
opening diameter, mm

Right atrioventricular   1.02[+ or -]0.07   1.28[+ or -]0.07   <0.0001
opening diameter, mm

Data are presented as mean[+ or -]SD
* Unpaired t test

Table 2. TNF-[alpha], IL-6 and caspase-3 levels after chronic
Cd exposure

                       Control         Cadmium
Variables               group           group        p *

TNF-[alpha],        402[+ or -]39   793[+ or -]26   <0.001
pg/g tissue

IL-6, pg/g tissue   150[+ or -]78   325[+ or -]65   <0.001

Caspase-3 levels,   12[+ or -]1.4   18[+ or -]1.3   <0.001
pmol/[micro]g/min

Cd--cadmium, IL-6--interleukin-6, TNF-[alpha]- tumor necrosis
factor alpha Data are presented as mean[+ or -]SD
* Unpaired t test
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Title Annotation:Original Investigation/Ozgun Arastirma
Author:Yazihan, Nuray; Kocak, Mehtap Kacar; Akcil, Ethem; Erdem, Onur; Sayal, Ahmet; Guven, Cengiz; Akyurek
Publication:The Anatolian Journal of Cardiology (Anadolu Kardiyoloji Dergisi)
Date:Sep 1, 2011
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