Inhibitory Effect of α-Lipoic Acid on Platelet Aggregation Is Mediated by PPARs
Inhibitory Effect of α-Lipoic Acid on Platelet Aggregation Is Mediated by PPARs
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DOI：
10.1021/jf103940u
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发表时间：
2011-04-13
影响因子：
6.1
通讯作者：
Chen, Ying-Tsung
中科院分区：
文献类型：
--
作者：
Chou, Tz-Chong;Shih, Ching-Yu;Chen, Ying-Tsung
过氧化物酶体增殖物激活受体（PPARs）同种型（α、β/δ和γ）存在于人血小板中，PPARs的激活抑制血小板聚集。α-硫辛酸（ALA）是一种天然存在于人类食物中的物质，据报道具有抗血小板活性。然而，潜在的ALA介导的血小板聚集抑制的机制仍然未知。本研究的目的是研究ALA的抗血小板活性是否是由PPARs介导的。ALA本身显著诱导血小板中的PPARalpha/gamma活化，并通过阻断花生四烯酸（AA）活化的血小板分泌PPARalpha/gamma来增加PPARalpha/gamma的细胞内量。此外，ALA显着抑制AA诱导的血小板聚集，Ca 2+动员，环氧合酶-1（考克斯-1）的活性，但增加环磷酸腺苷的生产在兔洗涤血小板。重要的是，ALA还增强了PPAR α/γ与蛋白激酶C α（PKC α）和考克斯-1的相互作用，同时抑制了静息和AA活化血小板中的PKC α活性。而同时加入选择性PPAR α拮抗剂（GW 6471）或PPAR γ拮抗剂（GW 9662）可明显逆转ALA对血小板的上述作用。总之，本研究提供了一种新的机制，通过该机制，ALA抑制血小板聚集是由PPAR α/γ依赖性过程介导的，该过程涉及与PKC α和考克斯-1的相互作用，增加环AMP形成，以及抑制细胞内Ca 2+动员。
Peroxisome proliferator-activated receptors (PPARs) isoforms (alpha, beta/delta, and gamma are present in human platelets, and activation of PPARs inhibits platelet aggregation. alpha-Lipoic acid (ALA), occurring naturally in human food, has been reported to exhibit an antiplatelet activity. However, the mechanisms underlying ALA-mediated inhibition of platelet aggregation remain unknown. The aim of this study was to investigate whether the antiplatelet activity of ALA is mediated by PPARs. ALA itself significantly induced PPAR alpha/gamma activation in platelets and increased intracellular amounts of PPAR alpha/gamma by blocking PPAR alpha/gamma secretion from arachidonic acid (AA)-activated platelets. Moreover, ALA significantly inhibited AA-induced platelet aggregation, Ca2+ mobilization, and cyclooxygenase-1 (COX-1) activity, but increased cyclic AMP production in rabbit washed platelets. Importantly, ALA also enhanced interaction of PPAR alpha/gamma with protein kinase C alpha (PKC alpha) and COX-1 accompanied by an inhibition of PKC alpha activity in resting and AA-activated platelets. However, the above effects of ALA on platelets were markedly reversed by simultaneous addition of selective PPAR alpha antagonist (GW6471) or PPAR gamma antagonist (GW9662). Taken together, the present study provides a novel mechanism by which ALA inhibition of platelet aggregation is mediated by PPAR alpha/gamma-dependent processes, which involve interaction with PKC alpha and COX-1, increase of cyclic AMP formation, and inhibition of intracellular Ca2+ mobilization.