Role of nuclear receptor signaling in platelets: antithrombotic effects of PPARβ
Role of nuclear receptor signaling in platelets: antithrombotic effects of PPARβ
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DOI：
10.1096/fj.05-4395fje
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发表时间：
2006-02-01
期刊：
影响因子：
4.8
通讯作者：
Mitchell, Jane A.
中科院分区：
文献类型：
--
作者：
Ali, Ferhana Y.;Davidson, Simon J.;Mitchell, Jane A.
过氧化物酶体增殖物激活受体 (PPAR) 是与类视黄醇 X 受体异二聚化的核受体，然后在转录水平调节许多靶基因的功能。已知三种 PPAR：α、β（有时称为 δ）和 γ。研究较好的是 PPARα 和 PPARγ，它们分别被贝特类药物和噻唑烷二酮类/格列酮类药物激活。现在人们相信 PPAR 的激活可能与预防人类心脏病和中风有关。在此，我们首次报道人类血小板含有 PPARβ，并且其选择性激活可抑制血小板聚集。 PPARβ 是前列环素的假定受体。前列环素是一种重要的抗血栓激素，与一氧化氮协同抑制血小板聚集。在当前的研究中，我们表明 PPARβ 配体同样与一氧化氮协同作用，抑制血小板聚集。这些观察结果挑战了我们对核受体的看法，因为 PPARβ 存在于无核血小板中并且具有活性。此外，这些数据表明前列环素的一些抗血栓作用可能是通过 PPAR 的激活介导的。因此，我们的结果将 PPARβ 确定为一种新型抗血小板靶点，可能介导血液中前列环素的一些作用。
Peroxisome proliferator‐activated receptors (PPARs) are nuclear receptors that heterodimerize with the retinoid X receptor and then modulate at the transcriptional level the function of many target genes. Three PPARs are known: α, β (sometimes called δ), and γ. The better studied are PPARα and PPARγ, which are activated by fibrates and thiazolidinediones/glitazones, respectively. It is now believed that activation of the PPARs could be associated with the prevention of heart attack and stroke in humans. Here we report, for the first time, that human platelets contain PPARβ and that its selective activation inhibits platelet aggregation. PPARβ is a putative receptor for prostacyclin. Prostacyclin is an important antithrombotic hormone that synergizes with nitric oxide to inhibit platelet aggregation. In the current study, we show that PPARβ ligands similarly synergize with nitric oxide to inhibit platelet aggregation. These observations challenge our view of a nuclear receptor because PPARβ is present and active in nonnucleated platelets. Furthermore, these data suggest that some of the antithrombotic actions of prostacyclin may be mediated via activation of PPARs. Thus, our results identify PPARβ as a novel antiplatelet target that may mediate some of the effects of prostacyclin in blood.