Simon T C, Makheja A N, Bailey J M
Department of Biochemistry and Molecular Biology, George Washington University School of Medicine Washington, D.C. 20037.
Prostaglandins Leukot Essent Fatty Acids. 1990 Dec;41(4):273-8. doi: 10.1016/0952-3278(90)90142-8.
Aortas from atherosclerotic rabbits have increased levels of 15-lipoxygenase, but the relationship between induction of this enzyme and the atherosclerotic process has not been defined. We found that dietary administration of cortisone acetate significantly suppressed atherosclerotic plaque formation in both Watanabe Heritable Hyperlipidemic (WHHL) and cholesterol-fed WHHL/NZW heterozygous rabbits. There was, however, no corresponding decrease in the elevated 15-lipoxygenase activity. In addition, the elevated 15-lipoxygenase activity in atherosclerotic rabbit aortas was uniformly distributed throughout the aorta, and was not preferentially localized in the lesions. These results indicate that induction of the 15-lipoxygenase is not necessarily causally related to plaque development, and that plaques are not the major source of the increased enzyme activity. However, the results confirm that hypercholesterolemia is a necessary condition for both atherosclerosis and 15-lipoxygenase induction, suggesting that perhaps the 15-lipoxygenase may represent a protective response to the hyperlipidemic stress. This possibility is supported by the finding that the induced 15-lipoxygenase converts linoleic acid, which is the predominant essential fatty acid in aorta, to 13-hydroxyoctadecadienoic acid (13-HODE). This compound is a chemorepellant factor for platelets, inhibits platelet thromboxane synthesis, and stimulates prostacyclin synthesis by endothelial cells.
动脉粥样硬化兔的主动脉中15-脂氧合酶水平升高，但这种酶的诱导与动脉粥样硬化进程之间的关系尚未明确。我们发现，给渡边遗传性高脂血症（WHHL）兔和喂食胆固醇的WHHL/NZW杂合兔口服醋酸可的松可显著抑制动脉粥样硬化斑块形成。然而，升高的15-脂氧合酶活性并没有相应降低。此外，动脉粥样硬化兔主动脉中升高的15-脂氧合酶活性在整个主动脉中均匀分布，并非优先定位于病变部位。这些结果表明，15-脂氧合酶的诱导不一定与斑块形成有因果关系，且斑块不是酶活性增加的主要来源。然而，结果证实高胆固醇血症是动脉粥样硬化和15-脂氧合酶诱导的必要条件，这表明15-脂氧合酶可能代表了对高脂血症应激的一种保护反应。这一可能性得到以下发现的支持：诱导产生的15-脂氧合酶将主动脉中主要的必需脂肪酸亚油酸转化为13-羟基十八碳二烯酸（13-HODE）。该化合物是血小板的化学排斥因子，抑制血小板血栓素合成，并刺激内皮细胞合成前列环素。
