A novel thromboxane receptor antagonist and synthase inhibitor, BM-573, reduces development and progression of atherosclerosis in LDL receptor deficient mice
A novel thromboxane receptor antagonist and synthase inhibitor, BM-573, reduces development and progression of atherosclerosis in LDL receptor deficient mice
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DOI：
10.1016/j.ejphar.2006.12.024
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发表时间：
2007-04-30
影响因子：
5
通讯作者：
Pratico, Domenico
中科院分区：
文献类型：
--
作者：
Cyrus, Tillmann;Yao, Yuemang;Pratico, Domenico
动脉粥样硬化是一种受多种介质影响的血管炎症性慢性疾病。其中，前列腺素类药物，包括前列环素和血栓素（Tx） A(2)，最近受到了广泛的关注。先前的研究表明，在载脂蛋白e缺乏的小鼠中，TxA(2)受体的拮抗或缺失延缓了早期动脉粥样硬化的发生，但在低密度脂蛋白（LDL）受体缺乏的小鼠中没有相关数据。在我们的研究中，我们测试了一种新型TxA(2)受体（TP）拮抗剂和合酶抑制剂BM-573对LDL受体缺陷小鼠动脉粥样硬化发生和进展的影响。为此，我们评估了BM-573治疗12周后对这些小鼠早期或已形成的主动脉粥样硬化病变的影响。在两种治疗中，BM-573虽然不影响体重、收缩压、血浆总胆固醇或甘油三酯水平，但它部分降低了TxA(2)，但不影响前列环素的生物合成。此外，BM-573显著减少早期动脉粥样硬化发生，并阻止已建立的动脉粥样硬化病变的进展。这些结果首次表明，这种双Tx抑制剂可以有效地减少LDL受体缺陷小鼠的动脉粥样硬化。他们还证明了一种新的概念，即这种治疗方法可以阻止疾病的进展并影响动脉粥样硬化斑块的细胞组成。(c) 2007 Elsevier B.V.版权所有
Atherosclerosis is a chronic inflammatory disease of the vasculature influenced by a variety of mediators. Among them, prostanoids, which include prostacyclin and thromboxane (Tx) A(2), have recently received a lot of attention. Previous studies demonstrated that antagonism or deletion of the receptor for TxA(2) retards early atherogenesis in apolipoprotein E-deficient mice, but no data are available in low-density lipoprotein (LDL) receptor deficient mice. In our study, we tested the effect of a novel TxA(2) receptor (TP) antagonist and synthase inhibitor, BM-573, on atherosclerosis development and progression in LDL receptor deficient mice. To this end, the effect of 12 weeks treatment with BM-573 on early or established aortic atherosclerotic lesions of these mice was assessed. In both treatments, while BM-573 did not affect body weight, systolic blood pressure, total plasma cholesterol or triglycerides levels, it partially reduced TxA(2) but did not affect prostacyclin biosynthesis. Moreover, BM-573 significantly decreased early atherogenesis and prevented progression of established atherosclerotic lesions. These results show for the first time that this dual Tx inhibitor is effective in reducing atherogenesis in the LDL receptor deficient mice. They also demonstrate the novel concept that this therapeutic approach halts the progression of the disease and influences the cellular composition of the atherosclerotic plaques. (c) 2007 Elsevier B.V. All rights reserved.