Abstract: BACKGROUND: Fish oil is one of mainly natural resources of n-3 fatty acids, which can inhibit cardiac allograft vasculopathy (CAV) and prolong the survival of cardiac allograft. But, the mechanism is unclear. Recent in vitro data suggested that n-3 fatty acids could inhibit the release of inflammatory transmitter by the activation of peroxisome proliferator-activated receptor-γ (PPARγ).
OBJECTIVE: To test the hypothesis that n-3 fatty acids from fish oil ameliorates CAV development via activating PPARγ.
METHODS: A total of 6 Lewis rats and 18 Fisher344 rats were randomly selected as heart donors. An additional 24 Lewis rats were randomly and equally divided into 4 groups. In isograft group, heart transplantation was performed among Lewis rats, without any drug. In low-dose fish oil-treated group, F344→Lewis transplantation was performed. At 1 day following surgery, 0.03 mL/kg fish oil was treated by gavage for 8 weeks. In high-dose fish oil-treated group, F344→Lewis transplantation was conducted. At 1 day following surgery, 0.06 mL/kg fish oil was treated by gavage for 8 weeks. In control group, F344→Lewis transplantation was conducted. Cyclosporine A was administrated by gavage for 8 weeks. In the low-dose and high-dose fish oil-treated groups, cyclosporine A (1.5 mg/kg) was given daily by intramuscular injection for 2 weeks following surgery. CAV was evaluated by histological examination. Activity of nuclear factor (NF) κ-B and PPARγ was assessed in homogenate. Contents of monocyte chemoattractant protein-1 and interferon-inducible protein 10 were measured by enzyme-labeled immunosorbent assay (ELISA). Chemokine receptor CCR2 and CXCR3 expression was determined by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR).
RESULTS AND CONCLUSION: All 24 receptor Lewis rats were survived following surgery. The donor heart could regularly beat at 8 weeks following transplantation. Compared with the isograft group, severe CAV was detected in the control group at 8 weeks. Compared with the control group, CAV was significantly relieved, the activity of PPARγ was significantly elevated, the activity of NF κ-B was significantly decreased, levels of intragraft monocyte chemoattractant protein-1 and interferon-inducible protein-10 were significantly reduced in the low-dose and high-dose fish oil-treated groups (P < 0.001, P < 0.05), especially in the high-dose fish oil-treated group (P < 0.05). There was no significant difference in expression of chemokine receptors CXCR3 in the low-dose and high-dose fish oil-treated groups and control group. Our results demonstrated that n-3 fatty acids from fish oil can attenuate CAV development, possibly through activating PPARγ and subsequently inhibiting the NF-κB activation, the chemokines secretion and its receptor expression in a dose-dependent fashion in rat models.