The thromboxane receptor antagonist S18886 but not aspirin inhibits atherogenesis in apo E-deficient mice - Evidence that eicosanoids other than thromboxane contribute to atherosclerosis
The thromboxane receptor antagonist S18886 but not aspirin inhibits atherogenesis in apo E-deficient mice - Evidence that eicosanoids other than thromboxane contribute to atherosclerosis
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DOI：
10.1161/01.atv.20.7.1724
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发表时间：
2000-07-01
影响因子：
8.7
通讯作者：
Cohen, RA
中科院分区：
文献类型：
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作者：
Cayatte, AJ;Du, Y;Cohen, RA
动脉粥样硬化涉及一系列复杂的因素，包括白细胞粘附和血小板血管活性因子。阿司匹林用于预防动脉粥样硬化的继发并发症，可抑制血小板生成血栓素 (Tx) A(2)。 TxA(2) 以及其他花生四烯酸产品，如前列腺素 (PG) H-2、PGF(2α)、羟基二十碳四烯酸和异前列腺素的作用，可以通过阻断血栓素 (TP) 受体来有效拮抗。本研究的目的是通过比较阿司匹林和TP受体拮抗剂ST8886的作用，确定血小板衍生的TxA(2)在动脉粥样硬化病变发展中的作用。在载脂蛋白 E 缺陷小鼠中，测定阿司匹林（30 mg(.)kg(-1.)d(-1)）或 S18886（5 mg(.)kg(-1.)d(-1)）治疗 11 周对主动脉根部动脉粥样硬化病变、细胞间粘附分子-1 (ICAM-1) 和 TxA(2) 代谢物 TxB(2) 血清水平的影响21周龄时。两种治疗都不影响体重或心脏重量或血清胆固醇水平。阿司匹林比S18886更大程度地显着降低血清TxB(2)水平，表明阿司匹林在预防血小板合成TxA(2)方面更有效。 S18886（而非阿司匹林）显着降低主动脉根部病变以及血清 ICAM-1 水平。 S18886 还可以阻止 TP 受体激动剂 U46619 刺激的培养人内皮细胞中 ICAM-1 表达的增加。这些结果表明，用阿司匹林抑制血小板 TxA(2) 合成对动脉粥样硬化形成或粘附分子水平没有显着影响。S18886 的作用表明，TP 受体的阻断通过独立于血小板衍生的 TxA(2) 的机制抑制动脉粥样硬化，可能是通过阻止粘附分子的表达，而粘附分子的表达受 TxA(2) 以外的类二十烷酸刺激。
Atherosclerosis involves a complex array of factors, including leukocyte adhesion and platelet vasoactive factors. Aspirin, which is used to prevent secondary complications of atherosclerosis, inhibits platelet production of thromboxane (Tx) A(2). The actions of TxA(2) as well as of other arachidonic acid products, such as prostaglandin (PG) H-2, PGF(2 alpha), hydroxyeicosatetraenoic acids, and isoprostanes, can be effectively antagonized by blocking thromboxane (TP) receptors. The purpose of this study was to determine the role of platelet-derived TxA(2) in atherosclerotic lesion development by comparing the effects of aspirin and the TP receptor antagonist ST8886. The effect of 11 weeks of treatment with aspirin (30 mg(.)kg(-1.)d(-1)) or S18886 (5 mg(.)kg(-1.)d(-1)) on aortic root atherosclerotic lesions, serum levels of intercellular adhesion molecule-1 (ICAM-1), and the TxA(2) metabolite TxB(2) was determined in apolipoprotein E-deficient mice at 21 weeks of age. Both treatments did not affect body or heart weight or serum cholesterol levels. Aspirin, to a greater extent than S18886, significantly decreased serum TxB(2) levels, indicating the greater efficacy of aspirin in preventing platelet synthesis of TxA(2). S18886, but not aspirin, significantly decreased aortic root lesions as well as serum ICAM-1 levels. S18886 also prevented the increased expression of ICAM-1 in cultured human endothelial cells stimulated by the TP receptor agonist U46619. These results indicate that inhibition of platelet TxA(2) synthesis with aspirin has no significant effect on atherogenesis or adhesion molecule levels, The effects of S18886 suggest that blockade of TP receptors inhibits atherosclerosis by a mechanism independent of platelet-derived TxA(2), perhaps by preventing the expression of adhesion molecules whose expression is stimulated by eicosanoids other than TxA(2).