A-002 (Varespladib), a phospholipase A2 inhibitor, reduces atherosclerosis in guinea pigs.
A-002 (Varespladib), a phospholipase A2 inhibitor, reduces atherosclerosis in guinea pigs.
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DOI：
10.1186/1471-2261-9-7
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发表时间：
2009-02-17
影响因子：
2.1
通讯作者：
Fernandez ML
中科院分区：
文献类型：
--
作者：
Leite JO;Vaishnav U;Puglisi M;Fraser H;Trias J;Fernandez ML
心血管疾病患者血清分泌型磷脂酶A2（sPLA 2）水平升高与动脉粥样硬化病变相关，提示sPLA 2酶参与了该疾病。在过度表达sPLA 2酶的小鼠中存在更晚期的动脉粥样硬化病变，表明它们参与动脉粥样硬化过程。因此，sPLA 2家族酶可为动脉粥样硬化的预防和治疗提供合理的靶点。因此，A-002（伐瑞拉迪），一种sPLA 2酶的抑制剂，被认为可以调节动脉粥样硬化的发展。24只豚鼠饲喂高饱和脂肪、高胆固醇饲料（0.25%）12周。动物每日经口灌胃给予A-002（n = 12）或溶媒（10%阿拉伯胶水溶液; n = 12）。12周后，处死动物，收集血浆、心脏和主动脉。通过酶法测量血脂，通过核磁共振测量脂蛋白颗粒大小，通过比色法测量主动脉细胞因子，通过组织学分析测量主动脉窦。血浆总胆固醇、高密度脂蛋白胆固醇和甘油三酯组间无差异。而治疗组的炎性细胞因子白细胞介素（IL）-10，IL-12和粒细胞-巨噬细胞集落刺激因子（GM-CSF）水平显著降低。与安慰剂组相比，该组主动脉中的胆固醇蓄积也显著降低了27%。主动脉窦的形态学分析显示，A-002治疗组动脉粥样硬化病变减少了24%。使用A-002可能对预防豚鼠饮食诱导的动脉粥样硬化具有有益作用。
The association of elevated serum levels of secretory phospholipase A2 (sPLA2) in patients with cardiovascular disease and their presence in atherosclerotic lesions suggest the participation of sPLA2 enzymes in this disease. The presence of more advanced atherosclerotic lesions in mice that overexpress sPLA2 enzymes suggest their involvement in the atherosclerotic process. Therefore, the sPLA2 family of enzymes could provide reasonable targets for the prevention and treatment of atherosclerosis. Thus, A-002 (varespladib), an inhibitor of sPLA2enzymes, is proposed to modulate the development of atherosclerosis. Twenty-four guinea pigs were fed a high saturated fat, high cholesterol diet (0.25%) for twelve weeks. Animals were treated daily with A-002 (n = 12) or vehicle (10% aqueous acacia; n = 12) by oral gavage. After twelve weeks, animals were sacrificed and plasma, heart and aorta were collected. Plasma lipids were measured by enzymatic methods, lipoprotein particles size by nuclear magnetic resonance, aortic cytokines by a colorimetric method, and aortic sinus by histological analyses. Plasma total cholesterol, HDL cholesterol and triglycerides were not different among groups. However, the levels of inflammatory cytokines interleukin (IL)-10, IL-12 and granulocyte-macrophage colony-stimulating factor (GM-CSF) were significantly reduced in the treatment group. This group also had a significant 27% reduction in cholesterol accumulation in aorta compared with placebo group. Morphological analysis of aortic sinus revealed that the group treated with A-002 reduced atherosclerotic lesions by 24%. The use of A-002 may have a beneficial effect in preventing diet-induced atherosclerosis in guinea pigs.
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影响因子：
5.3
作者：
Kimura-Matsumoto, Masayo;Ishikawa, Yukio;Ishii, Toshiharu
通讯作者：
Ishii, Toshiharu
影响因子：
37.8
作者：
Haghighat, Amir;Weiss, Daiana;Taylor, W. Robert
通讯作者：
Taylor, W. Robert
影响因子：
7.3
作者：
Draheim, SE;Bach, NJ;Wery, JP
通讯作者：
Wery, JP
影响因子：
4.2
作者：
FLYNN, TT;KUBENA, KS;RHEE, KS
通讯作者：
RHEE, KS
影响因子：
20.1
作者：
Hernández, M;Fuentes, L;Nieto, ML
通讯作者：
Nieto, ML