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Cardioprotective activity of Cladosiphon okamuranus fucoidan against isoproterenol induced myocardial infarction in rats.

ABSTRACT

Fucoidans, sulfated polysaccharides of brown algae, have attracted steady attention in the last few years as readily accessible biopolymers possessing a wide spectrum of biological activities. In this study, cardioprotective activity of fucoidan extracted from Cladosiphon okamuranus was evaluated in isoproterenol induced myocardial infarction in rats. Male Wistar albino rats (180 [+ or -] 25 g) were divided in to four groups of six animals each as follows: Group (1) control, Group (2) isoproterenol alone, Group (3) fucoidan alone and Group (4) fucoidan + isoproterenol. To evaluate the efficacy of fucoidan treatment against isoproterenol induced myocardial damage, biochemical parameters and histopathological studies were carried out. Isoproterenol administration produced severe myocardial damage and high lipid peroxidation level. On the contrary, fucoidan treatment reduced myocardial damage, which has been reflected by improvement in parameters such as creatinine phosphokinase (CPK), lactate dehydrogenase (LDH), alanine transaminase (ALT) and aspartate transaminase (AST). In addition, fucoidan improved the antioxidant defence system in treated animals and considerably reduced the oxidative stress exerted by isoproterenol. The reduction in oxidative stress in Group (4) was evident from the lipid peroxidation and antioxidant activities. Furthermore, the increase in the levels of total cholesterol, triglycerides and low density lipoprotein (LDL) and decrease in the levels of high density lipoprotein (HDL) was significantly reversed in Group (4), when compared with Group (2). The histopathological studies also showed that fucoidan treatment significantly minimized the damage induced by isoproterenol. Thus, fucoidan provide cardioprotection against isoproterenol induced myocardial infarction in rats.

ARTICLE INFO

Keywords: Fucoidan Isoproterenol Myocardial infarction Antioxidant enzymes

[C] 2010 Elsevier GmbH. All rights reserved.

Introduction

Myocardial infarction or heart attack is the leading cause of death for both men and women all over the world. It occurs when blood supply is insufficient to the myocardium, death of myocardial muscle occurs, a condition known as ischemia. Prolonged ischemia of the myocardium leads to necrosis, which is referred as myocardial infarction (Whellan 2005). Isoproterenol is a synthetic catecholamine and [beta]-adrenergic agonist which has been found to cause severe stress in the myocardium, resulting in infarct like necrosis of the heart muscle (Wexler and Greenberg 1978). These changes resemble the subendocardial laminar necrosis produced by myocardial ischemia in human (Chappel et al. 1959; Davies 1977) and therefore, it is a suitable model system to study myocardial infarction.

Cardiovascular dysfunction is a devastating disease which badly needs a medical breakthrough. Although modern drugs are effective in treating this condition, they are mostly accompanied with adverse effects. Marine plants, especially seaweeds are a largely unexplored reservoir of bioactive compounds. Brown seaweeds (Phaeophyceae) are known to produce different polysaccharides, namely alginates, laminarans and fucoidans. The latter polysaccharides usually contain large proportions of L-fucose and sulfate, together with minor amounts of other sugars like xylose, galactose, mannose and glucuronic acid. Fucoidans, a unique class of high-molecular-mass sulfated fucans exhibit anticoagulant, antithrombotic, antiproliferative, antitumoral antiangiogenesis and antivasculogenic properties (Boisson-Vidal et al. 1995). Since ancient times in the Okinawa region in Japan, Okinawa mozuku (Cladosiphon okamuranus), a brown seaweed, has historically been utilized as food and it is a main source of dietary fiber for the native population. Fucoidan extracted from Cladosiphon okamuranus has high L-fucose content and they can change the ratio of [CD4.sup.+]/[CD8.sup.+] cells and increase the number of cytotoxic T cells in mice (Jun et al. 2005). Moreover, fucoidan administration has no adverse effects on rats (Gideon and Rengasamy 2008). In this study, we examined the effects of fucoidan extracted from Cladosiphon okamuranus against isoproternol induced myocardial infarction in rats.

Materials and methods

Experimental animals and housing conditions

Male albino rats of Wistar strain (140-160 g) were obtained from King Institute, Chennai, India. These rats were allowed to adapt to the conditions of the animal house for 1 week before the experiment. The animals were maintained at about 25 [+ or -] 3 [degrees]C and allowed free access to standard laboratory diet and tap water ad libitum during the experimental period.

Source of fucoidan

Fucoidan of C. okamuranus was obtained from YSK-NB, Yaizu Suisankagaku Industry, Shizouka, Japan. The chemical composition of the extracted fucoidan is: fucose 40.2%, uronic acid 3.7%, neutral monosaccharides 24.7%, and sulfate 18.6%. The average molecular weight is 380,000 as determined by high performance steric exclusion chromatographic analysis (http://www.yskf.jp/yskf_en/yskf_en_ask.html).

Grouping of experimental animals

Male Wistar albino rats were divided into four groups of six animals each as follows: Croup (1) control; Group (2) isoproterenol treated; Group (3) fucoidan only; and Group (4) fucoidan + isoproterenol. Drug administration was as follows: fucoidan was given orally (150 mg/kg/day) for 7 days. This particular dosage was fixed after trying out different dosages for different days prior to isoproterenol treatment. The dosage 150 mg/kg daily for 7 days was selected on the basis of favorable modulation of histopathological and biochemical parameters. Isoproterenol was given intraperitoneally for 2 days (150 mg/kg/day) (Sathish et al. 2002). At the end of experimental period, the rats were sacrificed by cervical decapitation, blood was collected and the serum was used for the biochemical investigations.

Biochemical determinations

Estimation of serum enzymes: lactate dehydrogenase (LDH) by the method of King (1965), creatine phosphokinase (CPK) by the method of Okinaka etal. (1961), aspartate transaminase (AST) and alanine transaminase (ALT) by the method of Bergmeyer and Bernt (1974). Lipids in the serum were extracted by the method of Folch et al. (1957). Aliquots of the organic extracts were evaporated to dryness and used for the estimation of cholesterol (Parekh and Jung 1970), triglyceride (Rice 1970), LDL (Zilversmit and Davis 1957), and serum HDL (Lopes-Virella et al. 1977).

Immediately after the sacrifice, the hearts were excised and washed in ice-cold isotonic saline and blotted with a filter paper. Subsequently, the hearts were weighed and a portion of the tissue was homogenized in 0.1 M Tris-HCl buffer (pH 7.4). The homogenate was centrifuged at 7000 rpm for 15 min and the resulting supernatant was used for the estimation of the following parameters: lipid peroxidation (Okhawa et al. 1979), enzymatic antioxidants: GST (Habig et al. 1981), GPX (Rotruck 1973), SOD (Misra and Fridovich 1972), CAT (Sinha 1972) and non-enzymatic antioxidants: Reduced glutathione (Maron et al. 1979), [alpha]-tocopherol (Quaife et al. 1949) and Ascorbic acid (Omaye et al. 1979).

Histopathological studies

Histological evaluation was performed on lower portion of the heart. Specimen were fixed in 10% formalin and embedded in paraffin wax. Sections were cut at 4 [mu]m in thickness, stained with hematoxylin and eosin and viewed under light microscopy and examined the histological changes.

Statistical analysis

Data were evaluated by one-way analysis of variance (ANOVA) followed by least significant difference (LSD) test with SPSS/10 software. P values of less than 0.05 were considered to be significant difference between treatments. All values are expressed as mean [+ or -] S.D.

Results

Effect of fucoidan on marker enzymes

Table 1 shows the activities of marker enzymes of cardiac function (CPK, LDH, AST and ALT) in the serum of control and experimental rats. Compared to the control, serum CPK, LDH, AST and ALT were significantly increased in rats treated with isoproterenol. However, the increased enzyme activities due to isoproterenol treatment were not present in animals pre-treated with fucoidan for 7 days.
Table 1

Effect of fucoidan on marker enzymes of experimental animals.

Biochemical parameter  Control               Isoproterenol

CPK IU/L               220.35 [+ or -] 4.65  687.41 [+ or -] 11.25 (a),
                                             *

LDH IU/L                96.75 [+ or -] 3.87  287.41 [+ or -] 6.43 (a),
                                             *

AST IU/L               161.15 [+ or -] 5.45  246.67 [+ or -] 6.65 (a),
                                             *

ALT IU/L                37.25 [+ or -] 3.35   64.22 [+ or -] 2.65 (a),
                                             *

Biochemical parameter  Fucoidan              Fucoidan + isopreterenol

CPK IU/L               221.41 [+ or -] 8.25  298.36 [+ or -] 9.45 (b),
                                             *

LDH IU/L                95.57 [+ or -] 3.65  141.0 [+ or -] 5.34 (b),
                                             *

AST IU/L               158.65 [+ or -] 4.55  141.0 [+ or -] 5.34 (b),
                                             *

ALT IU/L                37.40 [+ or -] 2.25  54.33 [+ or -] 2.15 (b),
                                             *

Values are expressed as mean [+ or -] S.D. from six rats. Asterisk (*)
represents statistical significance.
(a) Compared with control.
(b) Compared with isoproterenol.
* P<0.05.


Effect of fucoidan on lipid peroxidation

Fig. 1 shows the levels of lipid peroxidation (LPO) in the serum and cardiac tissue of control and experimental animals. As can be seen, significant increase was observed in Group 2 rats in both serum and cardiac tissue in response to isoproterenol. Pre-treatment of the animals with fucoidan prevented this increase in response to isoproterenol.

[FIGURE 1 OMITTED]

Effect of fucoidan on enzymatic antioxidant activity of different experimental animals

The activities of antioxidant enzymes of the control and the experimental groups s are shown in Table 2. When compared with controls, the levels of tissue SOD, CAT, GST, GPX were reduced to 48%, 39%, 30% and 33% respectively in Group 2 rats treated with isoproterenol. While there was significant prevention in the reduction of the levels of enzymatic antioxidants by pretreatment with fucoidan in Group 4 rats.
Table 2

Effect of fucoidan on enzymatic antioxidants of experimental animals.

Biochemical parameter  Control               Isoproterenol

SOD                      7.11 [+ or -] 0.21   3.66 [+ or -] 0.18 (a), *
CAT                     66.51 [+ or -] 1.31  40.21 [+ or -] 1.14 (a), *
GST                    100.58 [+ or -] 3.58  70.94 [+ or -] 2.87 (a), *
GPX                      9.57 [+ or -] 0.13   6.08 [+ or -] 0.11 (a)

Biochemical parameter  Fucoidan              Fucoidan + isopreterenol

SOD                      7.31 [+ or -] 0.23   6.96 [+ or -] 0.15 (b), *
CAT                     69.04 [+ or -] 0.88  56.03 [+ or -] 1.80 (b), *
GST                    107.95 [+ or -] 2.59  82.11 [+ or -] 3.24 (b), *
GPX                      9.66 [+ or -] 0.26   8.06 [+ or -] 0.17 (b), *

Values are expressed as mean [+ or -] S.D. from six rats. Asterisk (*)
represents statistical significance. Unit for SOD; micromoles of
[H.sub.2][O.sub.2] decomposed per min/mg protein for CAT; n moles of
CDNB conjugated/min/g tissue for GST and microgram of glutathione
consumed/min/mg protein for GPX.
(a) Compared with control.
(b) Compared with isoproterenol.
* P < 0.05.


Effect of fucoidan on non-enzymatic antioxidant activity of different experimental animals

The levels of non-enzymatic antioxidants, viz., reduced glutathione, [alpha]-tocophorol and ascorbic acid were reduced to 14.79 nmol/g wet tissue, 1.71 mg/g wet tissue and 1.33 mg/g wet tissue respectively in Group 2 rats treated with isoproterenol. Treatment with fucoidan (Group 4) significantly prevented the reduction in the levels of non-enzymatic antioxidants (Table 3).
Table 3

Effect of fucoidan on non-enzymatic antioxidants of experimental
animals.

Biochemical parameter  Control              Isoproterenol

GSH                    41.46 [+ or -] 1.84  14.79 [+ or -] 2.70 (a), *
[alpha]-Tocopherol      2.86 [+ or -] 0.24   1.71 [+ or -] 0.14 (a), *
Ascorbic acid            2.8 [+ or -] 0.30   1.33 [+ or -] 0.17 (a), *

Biochemical parameter  Fucoidan             Fucoidan + isoproterenol

GSH                    43.18 [+ or -] 2.02  36.83 [+ or -] 1.70 (b), *
[alpha]-Tocopherol      2.95 [+ or -] 0.22    2.5 [+ or -] 0.10 (b), *
Ascorbic acid           2.59 [+ or -] 0.13   2.30 [+ or -] 0.23 (b), *

Values are expressed as mean [+ or -] S.D. from six rats. Asterisk (*)
represents statistical significance. Unit: nmol/g wet tissue for
reduced GSH and mg/g wet tissue for [alpha]-tocopherol and ascorbic
acid.
(a) Compared with control.
(b) Compared with isoproterenol.
* P < 0.05.


Effect of fucoidan on the lipid alterations of experimental animals

The results are cited in Table 4. The levels of total cholesterol, triglycerides, LDL and HDL were determined in the serum of the experimental animals. Treatment with isoproterenol caused a dramatic increase in the levels of total cholesterol, triglycerides, LDL and decrease in the levels of HDL. Fucoidan treatment reduced the levels of total cholesterol, triglycerides, LDL and increased the levels of HDL in Group 4 rats.

Histopathological observations

Fig. 2 shows the normal histology of the myocardium in control animals (A). Isoproterenol treated animals (Group 2) shows cardiac muscle separation and inflammatory infiltrate in to the myocardium (B). Group 3 rats treated with fucoidan only showed no changes (C). Fucoidan treatment (Group 4) showed mild muscle separation and few inflammatory cells (D).

[FIGURE 2 OMITTED]

Discussion

Seaweeds are known to produce a variety of compounds and several of them have been shown to possess biological activity of potential medicinal values (Moore 1978; Konig et al. 1994). For centuries, several seaweeds have been utilized traditionally as food supplements for various medical conditions. They have been used as antipyretic, antiseptic and for treatment of heart disease, skin problems, sunstroke, coughs, hemorrhoids, stomach ailments, nosebleeds, goiter and urinary diseases (Anggadiredja 1992). In the Chinese and Kampo (Japanese) medicines the dried stipe and fertile lamina of Laminaria, Undaria and Ecklonia were used as sources of iodine (Yubin and Guangmei 1998) and health food for new mothers to provide benefits for mothers and their children (Moon and Kim 1999). Moreover, brown algal preparations have been used as detoxifying agents (Gong et al. 1991; Shandala 1993).

Fucoidans are a group of naturally occurring polysaccharides found in brown seaweeds. Besides their anti-inflammatory (Sweeney et al. 2002; Charreau et al. 1997) and antiviral activity (Witvrouw and de Clercq 1997), fucoidan can modulate angiogenesis (Matou et al. 2002). Injection of these polyfucoses reduces intimal hyperplasia (Deux et al. 2002), promotes revascularization in a rat model of critical hind-limb ischemia (Luyt et al. 2003). The biological properties of fucoidan are a consequence of their charge density and are determined by detailed structural features (Pereira et al. 2002; Berteau et al. 2003). Because of their ionic structure, fucoidans have diverse biological properties, ranging from relatively simple mechanical support functions, to more intricate effects on cellular processes (Berteau and Mulloy 2003; Boisson-Vidal et al. 1995). Fucoidans bind proteins such as adhesion proteins (Haroun et al. 2002), growth factors (Thorlacius et al. 2000), cytokines (Sadir et al. 2001), and a variety of enzymes, including coagulation proteases (Mauray et al. 1998; Richard et al. 2006). As a result, they can participate, like glycosaminoglycans present on cell membrane, in cell adhesion, migration, proliferation and differentiation - the key steps of the angiogenic process.

The present study was aimed to investigate whether fucoidan of Cladosiphon okamuranus might differently affect isoproterenol induced myocardial infarction in rats. Isoproterenol induced a marked elevation in the serum levels of CPK, LDH, and transaminases in animals. On the contrary, fucoidan treatment 150 mg [kg.sup.-1] daily (Group 4) protected the structure and functional integrity of myocardial membrane as evident from the significant reduction in the elevated levels of these serum marker enzymes in the rats treated with fucoidan when compared to the isoproterenol treated rats. Increase in the activity of these enzymes is diagnostic indicators of myocardial infarction (Hearse et al. 1979) and are indicative of cellular damage and loss of functional integrity of cell membrane (Bhakta et al. 1999). The reversal of these enzyme activities by pretreatment with fucoidan indicates its therapeutic potential against myocardial infarction.

Fucoidan treatment also reduced lipid peroxidation activity and increased enzymatic and non-enzymatic antioxidants levels in rats, indicating a protective role for fucoidan against isoproterenol induced myocardial infarction (Fig. 1 and Table 2).The formation of free radicals and accumulation of lipid peroxides is one of the possible biochemical mechanisms for the myocardial damage caused by this catecholamine (Sushama Kumari et al. 1989). Free radical scavenging enzymes such as catalase, superoxide dismutase, glutathione peroxidase are the first line cellular defense against oxidative injury, decomposing [O.sub.2] and [H.sub.2][O.sub.2] before their interaction to form the more reactive hydroxyl radical ([OH*). The equilibrium between these enzymes is essential for the effective removal of oxygen stress in intracellular organelles. The second line of defense consists of the non-enzymatic scavenger's, viz., [alpha]-tocopherol and ascorbic acid, which scavenge residual free radicals escaping decomposition by the antioxidant enzymes. Improved antioxidant levels (enzymatic: SOD, CAT, GPx, GSH, GST and non-enzymatic: reduced glutathione, [alpha]-tocopherol, ascorbic acid) in the heart of animals treated with fucoidan indicates the potential of fucoidan in the treatment of myocardial infarction (Tables 2 and 3). Isoproterenol administration raised LDL cholesterol and decreased HDL cholesterol level in the serum of Group 2 animals (Table 4). Interestingly, treatment with fucoidan reversed the effects of isoproterenol. Increased total cholesterol, LDL cholesterol and decrease HDL cholesterol are associated with raised risk for myocardial infarction (Mediene-Benchekor et al. 2001). High level of circulating cholesterol, triglycerides and their accumulation in heart tissue are associated with cardiovascular damage. Hypertriglyceridemic patients at a risk for cardiovascular disease often develop a lipoprotein profile characterized by elevated triglyceride, dense LDL, and low HDL cholesterol, which causes myocardial membrane damage (Brewer 1999). Hypertriglyceridemia seen in isoproterenol treated rats is a condition observed in ischemic heart disease. The anti-hypertriglyceridemia activity of fucoidan, signify that the myocardial membrane is protected against isoproterenol induced damage. Further, histopathological findings confirmed the induction of myocardial infarction by isoproterenol and the protection rendered by fucoidan treatment to the cardiac muscle (Fig. 1).
Table 4

Effect of fucoidan on the lipid profile in the serum of experimental
animals.

Biochemical parameter  Control              Isoproterenol

Cholesterol (mg/dl)    61.21 [+ or -] 6.84  168.44 [+ or -] 11.65 (a),
                                            *
Triglycerides (mg/dl)  45.61 [+ or -] 6.82   90.60 [+ or -] 11.01 (a),
                                            *
LDL (mg/dl)             5.07 [+ or -] 0.51   21.11 [+ or -] 4.01 (a), *
HDL (mg/dl)             33.6 [+ or -] 3.42   20.01 [+ or -] 1.61 (a), *

Biochemical parameter  Fucoidan             Fucoidan + isoproterenol

Cholesterol (mg/dl)    59.70 [+ or -] 7.10  88.63 [+ or -] 5.89 (b), *
Triglycerides (mg/dl)  43.01 [+ or -] 5.65  58.75 [+ or -] 6.4 (b), *
LDL (mg/dl)             4.09 [+ or -] 0.31    7.5 [+ or -] 0.68 (b), *
HDL (mg/dl)            37.01 [+ or -] 4.21   28.1 [+ or -] 2.21 (b), *

Values are expressed as mean [+ or -] S.D. from six rats. Asterisk (*)
represents statistical significance.
(a) Compared with control.
(b) Compared with isoproterenol.
* P < 0.05.


Although fucoidans are high-molecular-weight polysaccharides, they exert biological effects in experimental animals after oral intake (Irhimeh et al. 2005). Fucoidans activate lympocytes and macrophages to render immune protection (Kelly 1999; Ho et al. 2000). They may exert their effects through gut-associated immunity before absorption, which is then transferred to the systemic immune response via lymph nodes and peripheral blood (Wu et al. 1998). Recent findings suggest that polysaccharides administered orally could also be absorbed partially via hepatic portal vein and central lacteals into general circulation with an intact molecular size. They accumulate in the mesenteric lymph nodes, Peyer's patches, spleen, liver and kidneys. Therefore, fucoidans have the potential to modulate the activity of the body's defense systems both at the mucous membrane and systemically (Yamashita et al. 1983; Kizu et al. 1998; Eun-Mi et al. 2005).

Collectively, our findings show fucoidan is non-toxic (Gideon and Rengasamy 2008) and could protect the cardiac cells from isoproterenol induced myocardial infraction. We hypothesise the protection of myocardium by fucoidan is likely due to the detoxification of isoprotenol through antioxidant defense system and alteration in lipid profile. Further studies are needed to determine the molecular mechanism by which fucoidan acts on the myocardium to beneficially affect the cardiovascular system. Studies in this line can open new avenues for novel seaweed compounds in the treatment of cardiovascular dysfunction.

Acknowledgments

The authors thank the Director, Centre for Advanced Studies in Botany, University of Madras for providing the laboratory facilities. We also thank Dr. C.S. Vijayalakshmi, M.D., D.C.P., Consultant Pathologist, Government Hospital, Royapettah, Chennai for her help in histopathological studies. We thank Dr. P. Bagavandoss, Department of Biological Science, Kent State University, Kent, OH, for critical reading of the manuscript.

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Paul Thomes (a), (b), *, Murugan Rajendran (a), Balu Pasanban (a), Ramasamy Rengasamy (a)

(a) Centre for Advanced Studies in Botany, University of Madras, Chennai 600025, India

(b) Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA

* Corresponding author at: Department of Internal Medicine, University of Nebraska, Omaha, NE, USA. Tel.: +1 402 201 6169.

E-mail address: pthomes@unmc.edu (P. Thomes).
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Author:Thomes, Paul; Rajendran, Murugan; Pasanban, Balu; Rengasamy, Ramasamy
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Geographic Code:9CHIN
Date:Dec 15, 2010
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