Cyclooxygenase-2-Derived Prostacyclin Regulates Arterial Thrombus Formation by Suppressing Tissue Factor in a Sirtuin-1-Dependent-Manner
Cyclooxygenase-2-Derived Prostacyclin Regulates Arterial Thrombus Formation by Suppressing Tissue Factor in a Sirtuin-1-Dependent-Manner
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DOI：
10.1161/circulationaha.112.097295
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发表时间：
2012-09-11
期刊：
影响因子：
37.8
通讯作者：
Tremoli, Elena
中科院分区：
文献类型：
--
作者：
Barbieri, Silvia S.;Amadio, Patrizia;Tremoli, Elena
背景：选择性环氧化酶(COX)-2抑制剂增加心肌梗死和血栓事件的风险，但其机制尚不完全清楚。方法与结果-我们发现氧化酶-2基因敲除小鼠与野生型小鼠相比，氯化铁诱导的动脉血栓形成明显增加。交叉输血实验排除了COX-2敲除血小板尽管对胶原蛋白和凝血酶的聚集反应增强，但对COX-2敲除小鼠动脉血栓形成增加负有责任的可能性。重要的是，我们观察到COX-2缺失降低了前列腺环素合成酶和生产以及过氧化物酶体增殖激活受体和SIRT1 （SIRT1）的表达，从而增加了组织因子（TF）的上调，组织因子是凝血的主要引发剂。用前列环素受体拮抗剂或过氧化物酶体增殖物激活受体拮抗剂治疗野生型小鼠，使其易于动脉血栓形成，降低SIRT1表达并增加TF活性。相反，外源性前置环素或过氧化物酶体增殖物激活受体激动剂完全逆转COX-2敲除小鼠的血栓表型，恢复正常的SIRT1水平并降低TF活性。此外，在野生型小鼠中，SIRT1的抑制增加了TF的表达和活性，促进了闭塞性血栓的产生，而SIRT1的激活足以降低COX-2敲除小鼠中TF的异常活性和血栓形成前状态。结论：前列腺环素/过氧化物酶体增殖物激活受体- δ通路调节SIRT1和TF不仅是控制动脉血栓形成的新机制，而且可能是治疗COX-2抑制剂相关的动脉粥样硬化血栓并发症的有用靶点。(循环。2012;126:1373 - 1384)。
Background-Selective inhibitors of cyclooxygenase (COX)-2 increase the risk of myocardial infarction and thrombotic events, but the responsible mechanisms are not fully understood.Methods and Results-We found that ferric chloride-induced arterial thrombus formation was significantly greater in COX-2 knockout compared with wild-type mice. Cross-transfusion experiments excluded the likelihood that COX-2 knockout platelets, despite enhanced aggregation responses to collagen and thrombin, are responsible for increased arterial thrombus formation in COX-2 knockout mice. Importantly, we observed that COX-2 deletion decreased prostacyclin synthase and production and peroxisome proliferator-activated receptor-and sirtuin-1 (SIRT1) expression, with consequent increased upregulation of tissue factor (TF), the primary initiator of blood coagulation. Treatment of wild-type mice with a prostacyclin receptor antagonist or a peroxisome proliferator-activated receptor-delta antagonist, which predisposes to arterial thrombosis, decreased SIRT1 expression and increased TF activity. Conversely, exogenous prostacyclin or peroxisome proliferator-activated receptor- agonist completely reversed the thrombotic phenotype in COX-2 knockout mice, restoring normal SIRT1 levels and reducing TF activity. Furthermore, inhibition of SIRT1 increased TF expression and activity and promoted generation of occlusive thrombi in wild-type mice, whereas SIRT1 activation was sufficient to decrease abnormal TF activity and prothrombotic status in COX-2 knockout mice.Conclusions-Modulation of SIRT1 and hence TF by prostacyclin/peroxisome proliferator-activated receptor-delta pathways not only represents a new mechanism in controlling arterial thrombus formation but also might be a useful target for therapeutic intervention in the atherothrombotic complications associated with COX-2 inhibitors. (Circulation. 2012;126:1373-1384.)