Synergistic favorable effect of eicosapentaenoic acid and statin on atherosclerosis

Background and Aims: Combination of Eicosapentaenoic Acid (EPA) and HMG-CoA reductase inhibitor (statin) are known to be an effective therapy for cardiovascular diseases, however, their biological roles in the favorable effect on adverse event have not been studied well. In this study, we aimed to investigate the effect of EPA and statins focusing on plaque formation in a rabbit plaque model. Methods: Rabbit carotid artery was injured with a balloon followed by feeding with a normal diet for 4 w and then with a high-cholesterol diet for 4 w. The rabbits were either received pitavastatin alone, EPA alone, combination (pitavastatin+EPA) or vehicle (control) for 4 w with a high-cholesterol diet. The injured carotid arteries were harvested and analysed morphometrically and immunohistochemically. Results: In control group, smooth muscle cells were located on the luminal side of the plaque and lipidrich macrophages accumulated in the center of the plaque expressing Matrix Metalloproteinase-9 (MMP-9), Tissue Factor (TF), and NF-kB, those are characteristic of unstable plaques. In contrast, EPA reduced the expression of TF and NF-kB and increased the expression of PPAR-α in the plaque. Pitavastatin also reduced the expression of MMP-9, TF, and NF-kB, but not PPAR-α in the plaque. Combination of pitavastatin and EPA significantly reduced the expression of MMP-9, TF, and NF-kB increasing the expression of PPAR-α resulting in the inhibition of intimal hyperplasia and plaque formation in carotid arteries. Conclusions: Pitavastatin and EPA synergistically played a role for inhibitory effect on plaque formation decreasing the expression of inflammation-related molecules and increasing the expression of PPAR-α in injured artery.