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Am J Physiol Heart Circ Physiol 294: H1452-H1458, 2008. First published January 25, 2008; doi:10.1152/ajpheart.01280.2007
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A comparison of the effects of fish oil and flaxseed oil on cardiac allograft chronic rejection in rats

Rgia A. Othman,1,3 Miyoung Suh,1 Gabor Fischer,2 Nazila Azordegan,1,3 Natalie Riediger,1,3 Khuong Le,1,3 Davinder S. Jassal,4,5 and Mohammed H. Moghadasian1,3

Departments of 1Human Nutritional Sciences and 2Pathology, 3Canadian Centre for Agri-Food Research in Health and Medicine, 4Institute of Cardiovascular Sciences, and 5Cardiology Division, Cardiac Sciences Department, University of Manitoba and Saint Boniface General Hospital Research Centre, Winnipeg, Canada

Submitted 1 November 2007 ; accepted in final form 22 January 2008


   ABSTRACT
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 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Both fish and flaxseed oils are major sources of different n-3 fatty acids. Beneficial effects of fish oil on posttransplantation complications have been reported. The current study aimed to compare the effects of flaxseed and fish oils in a rat cardiac allograft model. Male Fischer and Lewis rats were used as donors and recipients, respectively, to generate a heterotopic cardiac allograft model. Animals were randomly assigned into three groups and fed a diet supplemented with 1) 5% (wt/wt) safflower oil (control, n = 7), 2) 5% (wt/wt) flaxseed oil (n = 8), or 3) 2% (wt/wt) fish oil (n = 7), and an intraperitoneal injection of cyclosporine A (CsA; 1.5 mg·kg–1·day–1) over 12 wk. Body weight, blood pressure, plasma levels of lipids, CsA, select cytokines, as well as graft function and chronic rejection features were assessed. Body weight and blood CsA levels were similar among the groups. Relative to controls, both treated groups had lower systolic and diastolic blood pressure and plasma levels of macrophage chemotactic protein-1. Treatment with fish oil significantly (P < 0.05) lowered plasma levels of triglycerides, total cholesterol, and LDL-cholesterol. HDL-cholesterol concentrations were significantly higher (P < 0.05) in the flaxseed oil-treated group compared with the other two groups. Both flaxseed oil and fish oil may provide similar biochemical, hemodynamic, and inflammatory benefits after heart transplantation; however, neither of the oils was able to statistically significantly impact chronic rejection or histological evidence of apparent cyclosporine-induced nephrotoxicity in this model.

inflammation; hypertension

CHRONIC REJECTION REMAINS as one of the major problems in solid organ transplantation, despite the successful use of immunosuppressive agents (25). Long-term use of cyclosporine A (CsA) may contribute to chronic rejection through increasing the risk of hyperlipidemia (5), hypertension (51), and nephrotoxicity (41, 46). Conversely, fish oil may offset these side effects of CsA by improving blood lipid profile (23), inflammatory cytokine levels (16), blood pressure (20), and renal function (21). These beneficial effects of fish oil may be related to the n-3 fatty acids (n-3 FAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).

Flaxseed oil is another major source of an n-3 FA, namely, {alpha}-linolenic acid (ALA). When compared with EPA and DHA, ALA is shorter and has fewer double bonds. Although lower level organisms can convert ALA to EPA and DHA, this conversion in humans and animals seems to be less efficient (28). However, both the n-3 and n-6 FAs are essential for humans and animals. The n-3 and n-6 FAs, EPA and arachidonic acid, respectively, also compete with each other in the cyclooxygenase and lipooxygenase pathways for generation of eicosanoids, such as leukotrienes, prostaglandins, and thromboxanes. Eicosanoids derived from n-6 FAs are generally proinflammatory and proaggregatory, whereas those produced from n-3 FAs have no or limited such effects (45). The ratio of dietary n-6 to n-3 FAs, therefore, determines the type and biological efficacy of eicosanoids, which in turn impact the immune, inflammatory, and thrombotic responses (43). This has been one of the rationale for recent recommendations of reducing the ratio of n-6 to n-3 FAs to as low as 2 to 1. To comply with this recommendation, one must consume more n-3 FAs. The dietary sources of n-3 FAs are not as abundant as those for n-6 FAs. Some restrictions, including resources, availability, cost, taste, personal preference, and others, may further limit consumption of EPA and DHA. Thus plant-derived n-3 FAs may be an excellent alternative for increasing consumption of n-3 FAs in the general population or in subjects with cardiovascular disorders.

Although the biological effects of ALA may not be the same as those for EPA and DHA, we have recently demonstrated that flaxseed products exhibit antiatherosclerotic activities in cholesterol-fed rabbits and LDL-receptor knockout (KO) mice (10, 11). The mechanisms underlying these beneficial properties of flaxseed may be mediated through its beneficial effects on lipid metabolism, platelet function, inflammation, endothelial cell function, and arrhythmia (36). These mechanisms may also contribute to posttransplant complications. The aim of the present study was to investigate whether the effects of dietary flaxseed oil are comparable with those of fish oil on posttransplant complications and graft survival in a rat cardiac allograft model.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animals and diets. Forty-four, 5-wk-old Fischer-344 and Lewis rats (200 to 350 g) were purchased from Charles River (Montreal, QC, Canada). All rats were housed under standard conditions with ad libitum access to chow and water. After 1-wk acclimation, standard abdominal heterotopic cardiac transplantation procedures were performed to generate 22 allografts using Lewis rats as recipients and Fischer-344 rats as donors (39). After complete recovery from surgery, the rats were randomly assigned into three treatment groups and fed PicoLab rat diet (Ren's feed and supply) supplemented with 1) 5% (wt/wt) safflower oil (control group, n = 7), 2) 5% (wt/wt) flaxseed oil (flaxseed oil-treated group, n = 8), or 3) 2% (wt/wt) fish oil (n = 7) for 12 wk. The composition of the experimental diets is summarized in Table 1. Flaxseed and safflower oils were purchased from DYETS (Bethlehem, PA), whereas fish oil (EPAX 5500 TG) was a generous gift from EPAX AS (Lysaker, Norway). All of the animals were treated with a daily intraperitoneal injection of 1.5 mg/kg CsA (Neoral, Novartis). Body weight was recorded weekly, and blood samples were collected from the jugular veins of lightly anesthetized animals at week 6. Graft function was assessed weekly in a blinded fashion by palpation and rated on a scale of 0 to 4, with 4 indicating vigorous beats and 0 denoting the absence of beats as previously described (9, 15). At the end of the study, the rats were euthanized using CO2, final blood samples were collected through cardiac puncture, a complete autopsy was performed, and both native hearts and the grafts were collected and processed for further analyses. The Animal Care Committee on the Use of Animals in Research at the University of Manitoba approved the study.


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  		Table 1. Nutrient contents of the experimental diets per 100 g

 
Plasma lipids and lipoprotein levels. Plasma samples taken at week 6 of the study were used to estimate the levels of triglycerides (TGs) and total cholesterol (TC) using standard enzymatic assays as previously described (32). Plasma lipoprotein fractions in final blood samples were quantified by the HPLC method as previously described (50). Briefly, aliquots of plasma were injected into the system, and fractions corresponding to chylomicrons, very low-density lipoprotein (VLDL), LDL, and HDL were collected. TC and TG concentrations in these fractions were analyzed using standard enzymatic assays. With the use of this system, the lipoprotein particle size was also estimated as previously described (38). The non-HDL cholesterol was calculated by the subtraction of HDL-cholesterol levels from TC levels. Similarly, TC-to-HDL and LDL-to-HDL ratios were calculated.

Plasma cytokines. Plasma samples taken at week 6 were pooled to generate three samples for each experimental group. The pooled samples were assayed using a rat cytokine array (RayBiotech) as previously described (53).

Cyclosporine blood concentrations. Blood samples were sent to the Winnipeg Health Science Centre for determination of blood CsA levels using standard clinical laboratory methods.

Blood pressure measurement. To minimize the effects of stress and its impact on blood pressure, the rats were accustomed to training sessions for 3 to 4 days before blood pressure measurements. Blood pressure was measured using the tail-cuff method in the conscious state as previously reported (8). These procedures were performed in a quiet, dark place and at the same time of day to avoid the influence of the circadian rhythm.

Histological examination. At the time of death, both native hearts and graft tissues as well as the kidneys and other tissues were appropriately collected and processed for histological examinations as previously described (30). Serial sections were cut and stained with hematoxylin and eosin and Masson's trichrome (31). The status of graft rejection was scored using the Billingham rejection grading system (47), including 0 (no rejection) to 3 (severe rejection). Further pathological assessments were made with regard to vascular and myocardial remodeling, necrosis, fibrosis, and other aspects of chronic rejection phenomenon. Similarly, cross sections of the kidneys were stained with hematoxylin and eosin, Masson's trichrome, and periodic acid-Schiff (PAS) for evaluation of evidence for chronic cyclosporine-induced nephrotoxicity (alterations in arterioles, glomeruli, and tubulointerstitium) as described previously (46).

Heart lipids. Lipid contents of graft and native heart tissues were extracted according to Folch et al. (13). Thin-layer chromatography with G-silica gel (20 x 20 cm) was used to separate phospholipids, cholesterol, TG, and monoglyceride as previously described (48). The plates were visualized with 0.01% (wt/vol) aniline-naphthalene-sulfonic acid in water and then quantified by using the Fluorochem FC digital imaging system (Alpha Innotech, San Leandro, CA).

Statistical analysis. The data are reported as means ± SD. Statistical analysis was performed using one-way ANOVA followed by the application of the Tukey test for comparisons across the three experimental groups. Repeated-measures analysis was used to detect the effects of time and diets on plasma TC levels. For the heart and graft lipids, two-way ANOVA was used to identify the main effects of graft and diet. The {chi}2-test was used to determine the overall effects of the treatment protocols on the distribution of various grades of rejection among the three groups of the rats. P < 0.05 was considered significant.


   RESULTS
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DISCUSSION
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Body weight. As demonstrated in Fig. 1, all rats in the experimental groups gained weight similarly throughout the study period. All of the animals appeared healthy and behaved normally during the course of the study.


Figure 1
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  		Fig. 1. Mean body weights by groups and experimental course. Body weight in all groups remained comparable during the study period. Fish, fish oil group; Flax, flaxseed oil group.

 
Blood pressure and heart rates. Dietary supplementation with either flaxseed oil or fish oil caused significant reductions in blood pressure. At week 6, both flaxseed- and fish oil-treated rats exhibited significant reductions in systolic blood pressure (122 ± 9 and 109 ± 15 vs. 150 ± 19 mmHg, P <0.05) and diastolic blood pressure (89 ± 7 and 84 ± 9 vs. 114 ± 3 mmHg), compared with controls (Fig. 2). These changes were accompanied by similar reductions in heart rates in both treated groups compared with the controls (data not shown).


Figure 2
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  		Fig. 2. Effects of dietary protocols on systolic (SBP) and diastolic blood pressure (DBP) at weeks 6 and 12. Values are means ± SD. ***P < 0.001 compared with the control group.

 
Plasma lipids and lipoprotein profiles. As shown in Table 2, at weeks 6 and 12, the fish oil-treated group had significantly lower TC levels compared with either flaxseed or control groups. The levels of plasma non-HDL, LDL, and LDL/HDL-to-cholesterol ratio were significantly (P < 0.05) reduced in the fish oil-treated group compared with those in the control group. In addition, a significant decrease (–22%) in LDL/HDL-to-cholesterol ratio was observed in the flaxseed oil-treated group relative to the controls; this may be due to a significant increase (19%) in HDL-cholesterol levels in the flaxseed oil-treated group. VLDL, LDL, and HDL particle size remained comparable among the groups. Furthermore, a significant reduction in plasma TG concentrations relative to either controls (–35%) or flaxseed oil-treated (–47%) animals was observed at week 6 in the fish oil-treated group; the flaxseed-treated animals had slightly higher levels of TG compared with controls (84.2 vs. 70.4, mean values).


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  		Table 2. Lipoprotein size and cholesterol concentrations plus cyclosporine levels at the end of the study

 
Plasma cytokine concentrations. Both flaxseed and fish oils significantly (P < 0.05) reduced plasma levels of macrophage chemotactic protein-1 (MCP-1) compared with the controls. No statistically significant differences, however, were observed in IL-1β, IL-4, IL-6, IFN-{gamma}, or TNF-{alpha} levels among the experimental groups (Table 3).


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  		Table 3. Effects of diet on plasma cytokine profiles at week 6

 
Histology and rejection grades. Histological examinations of the sections obtained from the graft tissues showed variations among the experimental groups in regard to features of chronic rejection. These included edema, inflammatory cell infiltration in both interstitial and perivascular areas (mostly mononuclear cells and scattered multinucleated giant cells), presence of fibrosis, and cardiomyocyte necrosis (myocytolysis). These features were the basis of defining the grades of chronic rejection based on the Billingham rejection grading system (47). Figure 3 illustrates representative sections with grade 0 (Fig. 3A), grade 1 (Fig. 3B), grade 2 (Fig. 3C), and grade 3 (Fig. 3D). Whereas Fig. 3A shows almost normal-looking architecture of cardiac morphology, Fig. 3D presents multifocal injuries, including massive inflammation, complete destruction of myocardium, and extensive extracellular matrix deposition. Sections from high-grade rejection grafts also showed features of degenerative changes, such as calcification, ossification, and hemosiderin pigment deposition. Four animals in the flaxseed oil group and three animals in the control group showed a grade 3 of rejection; none of the animals in these two groups showed grade 0. Conversely, none of the animals in the fish oil group demonstrated grade 3 rejection and two animals demonstrated grade 0 rejection. However, {chi}2-test did not detect statistically significant differences in the distribution of rejection grades among the groups (P > 0.05). Sections from the graft with high-grade rejection status consistently had prominent endothelium with vacuolation, perivascular fibrosis, arterial wall thickening (most likely medial thickening), and evidence of vascular wall necrosis or degeneration. All of the native hearts, regardless of the experimental treatments, showed normal cardiac morphology. The distribution of chronic rejection grades among the experimental groups is summarized in Table 4. Figure 4 demonstrates representative photomicrographs of sections from the kidneys highlighting apparent cyclosporine-induced nephrotoxicity. The arrows in Fig. 4, A–C, show similar extents of PAS-positive hyaline thickening of the arteriolar wall at the entry to the glomerulus in all three groups of animals. Similarly, arrows in Fig. 4, D–F, point to similar degrees of mild focal interstitial fibrosis as well as evidence for focal atrophy of renal tubules in all of the three groups of the rats.


Figure 3
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  		Fig. 3. Representative photomicrographs of sections taken from the grafts with various degrees of rejection. A: normal looking hearts showing no evidence of rejection (grade 0). B: grade 1 rejection showing scattered mixed inflammatory cells (arrow) with mildly damaged cardiomyocytes and a coronary artery (double-headed arrow). C: grade 2 rejection presenting increased inflammation and mild architectural disarray (double-headed arrow). D: grade 3 rejection presenting prominent inflammatory infiltrate, major tissue destruction and calcification (arrow) along with increased apparently apoptotic bodies. Hematoxylin and eosin staining used (x400).

 

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  		Table 4. Distribution of chronic rejection grades according to Billingham criteria among the experimental groups

 

Figure 4
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  		Fig. 4. Representative photomicrographs of cross sections taken from the kidneys of control (A and D), fish oil treated (B and E), and flaxseed oil treated (C and F) stained with periodic acid-Schiff (PAS; A–C, x400) and Masson's trichrome (D–F, x400). PAS-positive narrowing of the arteriolar wall (arrows) is illustrated to be similar in all of 3 groups of animals. Similarly, a comparable extent of focal interstitial fibrosis and evidence of focal tubular atrophy are illustrated in all 3 groups of animals (arrows).

 
Heart and graft lipids. Lipid distribution was different between the native hearts and the graft tissue in each experimental group. For example, Fig. 5A presents statistically significant lower levels of percent phospholipids in the graft tissue compared with that in the native heart tissues from the fish oil-treated animals. Contrarily, the levels of TGs and monoglycerides were significantly higher in the graft tissues compared with those in the native hearts in all of the experimental groups (Fig. 5, C and D). On the other hand, the levels of cholesterol remained comparable between the native hearts and the graft tissues in all of the experimental groups (Fig. 5B).


Figure 5
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  		Fig. 5. Lipid fractions of graft and native hearts. Values represent means ± SD (n = 5 to 6 animals). Significant effects were identified by 2-way ANOVA procedures for graft and diet. *P < 0.02, value for group is statistically significantly different from that in other corresponding groups. G, graft tissue; N, native heart tissue; PL, phospholipids; TG, triglycerides; MG, monoglyceride; Chol, cholesterol; Cont, control.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
We have compared the effects of dietary flaxseed oil with those of fish oil on posttransplant complications in a Fisher-to-Lewis rat heterotopic cardiac transplant model (9, 24, 26a). Our data suggest that both oils may beneficially reduce some of the posttransplant complications, including biochemical and hemodynamic parameters and inflammatory status.

In the present study, treatment with either flaxseed oil or fish oil was associated with a significant decline in systolic and diastolic blood pressure compared with controls. Similarly, a significant attenuation in heart rates was observed in both treated groups (flaxseed and fish oils) as early as 12 wk. Consistent with our findings, fish and flaxseed oils resulted in attenuations in blood pressure in heart transplant recipients (3, 20, 52), hypertensive rats (29), and rats with renal ablation (22). The mechanism underlying hypertension-lowering effects of oils rich in n-3 FAs might be related, at least in part, to an induction of vasodilation due to an improved prostaglandin profile (12), inhibition of angiotensin-converting enzyme activity, reduction of angiotensin II production, or an improvement in endothelial nitric oxide production (33).

Elevated concentrations of plasma TC and TGs are a risk factor for transplant coronary atherosclerosis (40). In agreement with previous reports (14, 19, 55), fish oil treatment was associated with reductions in TGs, TC, VLDL, non-HDL, and LDL-cholesterol levels. Furthermore, the ratio of LDL to HDL was significantly reduced in both treated groups compared with controls. Other studies have also reported lipid-lowering effects of ALA in hamsters (35). Therefore, one may propose that both oils (fish and flaxseed) may have antiatherogenic properties, regardless of the type of n-3 FAs, through beneficial modifications in lipoprotein metabolism. It is interesting to note that we have observed a strong association between the amount of oil in dietary flaxseed and the degree of prevention of atherosclerosis in LDL-receptor KO mice (10). However, fish oil did not prevent atherosclerosis in apolipoprotein E-KO mice (54). An increased atherogenic lipoprotein profile has been shown in both clinical and experimental models of heart transplantation (4, 44). This could be one of the main factors contributing to allograft chronic rejection. However, in the present study, neither of the oils statistically significantly prevented chronic rejection. The lack of statistically significant differences among the groups could be due to a relatively small sample size (n = 7). Other studies did not report such an effect for fish oil in either rat or rabbit models of cardiac transplantation (55, 56). On the other hand, the benefits of fish oil in the prevention of chronic rejection were reported in kidney transplant recipients (21). Regardless, the lower number of rejection grades in the fish oil group might be because of an incorporation of adequate amounts of EPA and DHA into the phospholipid bilayer of the graft tissue, resulting in a modification of membrane fluidity, intracellular signal transduction, production of less harmful eicosanoids, less proinflammatory cytokine release, and reducing cytokine receptor interaction. The net outcome of these events will be reduced T-cells recruitment and the extent of inflammation (2, 26). Neither fish oil nor flaxseed oil was able to prevent apparent cyclosporine-induced nephrotoxicity as evaluated by histological examinations.

Marine and plant n-3 FAs have previously been shown to lower proinflammatory cytokines (7, 34, 42, 57). MCP-1 is a chemoattractant cytokine that is involved in the activation and recruitment of monocytes (1). In this study, both fish and flaxseed oils equally reduced plasma MCP-1 levels (–12%) compared with controls. It is suggested that the anti-inflammatory actions of these oils may be due to their impact on transcription factors influencing gene expression (37, 49) and/or synthesis of eicosanoids (6, 17).

Available evidence suggests that the cardioprotective mechanism of n-3 FAs depends on their presence in myocardial cell membranes (27). Thus one may suggest that an incorporation of EPA and DHA into graft cell membranes might play a role in better graft function and survival in the fish oil-treated animals. On the other hand, such effects might not be produced by ALA or the conversion of ALA to EPA, and DHA was not sufficient enough to generate biological effects in the flaxseed oil-treated animals. Furthermore, it is evident that the extent of other benefits of ALA, including reductions in blood pressure and anti-inflammatory state, were not adequate to prevent chronic rejection in this model. Another interesting observation from this study is a lack of association between graft TG contents and chronic rejection. The fish oil-treated animals showed a high amount of graft TGs and a low grade of chronic rejection, whereas this was opposite in the other two groups of animals. Based on our own previous observations and the available literature, it is unlikely that these differences observed between grafts and native hearts are related to the strain of animals used as donors and recipients. Future studies warrant the understanding of the mechanisms of this observation.

In conclusion, this study reports that both dietary flaxseed oil and fish oil may reduce the extent of lipid, hemodynamic, and inflammatory abnormalities after heart transplantation in rats. However, these apparent beneficial changes were not associated with significantly reduced chronic rejection states or apparent histological evidence of cyclosporine-induced nephrotoxicity. Further studies will help understand whether the extent of incorporation of long-chain n-3 FAs in graft tissues is important for prevention of chronic rejection.


   GRANTS
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported in part by the Heart and Stroke Foundation of Canada, the Natural Engineering and Science Research Council of Canada, the Canadian Institutes of Health Research, and the Canada Foundation for Innovation (to M. H. Moghadasian). R. A. Othman is a recipient of the Libya's Scholarship for Graduate Studies, and N. Riediger is a recipient of the National Sciences and Engineering Research Council Graduate Scholarship.


   FOOTNOTES
 

Address for reprint requests and other correspondence: M. H. Moghadasian, St. Boniface Hospital Research Ctr., Pathology Research Laboratory, 351 Tache Ave., Winnipeg, MB, R2H 2A6, Canada (e-mail: mmoghadasian{at}sbrc.ca)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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