Ii Hiromi, Hontani Naoya, Toshida Issei, Oka Mayuko, Sato Takashi, Akiba Satoshi
Department of Pathological Biochemistry, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
Biol Pharm Bull. 2008 Mar;31(3):363-8. doi: 10.1248/bpb.31.363.
Matrix metalloproteinase-9 (MMP-9) is involved in atherogenesis, and the production of MMP-9 in macrophages is considered to be mediated by the arachidonic acid cascade. The present study examined the possible involvement of group IVA phospholipase A2 (IVA-PLA2), a key enzyme in the arachidonic acid cascade, in the production of MMP-9 induced by oxidized low-density lipoprotein (oxLDL) in macrophages and high-fat diet-induced formation of atherosclerotic lesions using IVA-PLA2-deficient mice (C57BL/6 background). In wild-type mouse peritoneal macrophages, oxLDL induced an increase in MMP-9 in the culture medium. The oxLDL-promoted production of MMP-9 was markedly reduced in IVA-PLA2-deficient macrophages compared to wild-type macrophages. Feeding of wild-type mice with a high-fat diet caused the formation of early atherosclerotic lesions in the aortic root with increases in MMP-9 and macrophages in the lesions and with higher serum levels of total cholesterol. Such lesions were apparently less severe in IVA-PLA2-deficient mice fed a high-fat diet, despite higher total cholesterol levels. Under the conditions, a high-fat diet reduced the serum levels of high-density lipoprotein-cholesterol (HDL-C) in wild-type mice. However, IVA-PLA2-deficient mice fed a high-fat diet were protected against the decrease in HDL-C levels. The present results suggest that IVA-PLA2 is involved in the oxLDL-induced production of MMP-9 in macrophages and the high-fat diet-induced formation of early atherosclerotic lesions. The protection against the lesions in IVA-PLA2-deficient mice may be ascribable, in part, to the impaired production of MMP-9 and/or the maintained levels of HDL-C.
基质金属蛋白酶-9（MMP-9）参与动脉粥样硬化的形成，巨噬细胞中MMP-9的产生被认为是由花生四烯酸级联反应介导的。本研究使用IVA磷脂酶A2（IVA-PLA2）基因缺陷小鼠（C57BL/6背景），研究了花生四烯酸级联反应中的关键酶IVA-PLA2在巨噬细胞中氧化型低密度脂蛋白（oxLDL）诱导的MMP-9产生以及高脂饮食诱导的动脉粥样硬化病变形成过程中可能发挥的作用。在野生型小鼠腹腔巨噬细胞中，oxLDL可诱导培养基中MMP-9水平升高。与野生型巨噬细胞相比，IVA-PLA2缺陷型巨噬细胞中oxLDL促进的MMP-9产生明显减少。给野生型小鼠喂食高脂饮食会导致主动脉根部形成早期动脉粥样硬化病变，病变部位的MMP-9和巨噬细胞增加，血清总胆固醇水平升高。尽管总胆固醇水平较高，但在喂食高脂饮食的IVA-PLA2缺陷型小鼠中，此类病变明显较轻。在此条件下，高脂饮食降低了野生型小鼠血清高密度脂蛋白胆固醇（HDL-C）水平。然而，喂食高脂饮食的IVA-PLA2缺陷型小鼠对HDL-C水平的降低具有抵抗作用。本研究结果表明，IVA-PLA2参与了巨噬细胞中oxLDL诱导的MMP-9产生以及高脂饮食诱导的早期动脉粥样硬化病变形成。IVA-PLA2缺陷型小鼠对病变的抵抗作用可能部分归因于MMP-9产生受损和/或HDL-C水平维持。
