12(S)-HETrE, a 12-Lipoxygenase Oxylipin of Dihomo-γ-Linolenic Acid, Inhibits Thrombosis via Gαs Signaling in Platelets.
12(S)-HETrE, a 12-Lipoxygenase Oxylipin of Dihomo-γ-Linolenic Acid, Inhibits Thrombosis via Gαs Signaling in Platelets.
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DOI：
10.1161/atvbaha.116.308050
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发表时间：
2016-10
期刊：
影响因子：
--
通讯作者：
Holinstat M
中科院分区：
文献类型：
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作者：
Yeung J;Tourdot BE;Adili R;Green AR;Freedman CJ;Fernandez-Perez P;Yu J;Holman TR;Holinstat M
膳食补充多不饱和脂肪酸（PUFAs）已被广泛用于风险个体CVD的一级和二级预防;然而，由于缺乏机制和体内证据，PUFAs的心脏保护益处仍存在争议。我们提出了直接证据，即ω-6 PUFA，二高-γ-亚麻酸（DGLA），通过12-脂氧合酶（12-LOX）将DGLA氧化为其还原氧化脂质形式12（S）-HETrE，抑制血小板活化和血栓形成，表现出体内心脏保护作用。DGLA在野生型小鼠中抑制离体血小板聚集和Rap 1活化，但在缺乏12-LOX表达的小鼠（12-LOX−/−）中不抑制。类似地，用DGLA处理的野生型小鼠能够减少激光诱导的提睾肌小动脉损伤后的血栓生长（血小板和纤维蛋白积累），但不能减少12-LOX−/−小鼠，支持介导DGLA对血小板介导的血栓形成的抑制作用的12-LOX需求。当用12（S）-HETrE直接处理时，血小板活化和血栓形成也被抑制。重要的是，两种止血模型，尾部出血和提睾肌的小动脉破裂，在12（S）-HETrE处理后显示止血没有改变。最后，12（S）-HETrE保护的机制被证明是通过人血小板中的Gα s连接的GPCR途径介导的。这项研究提供了第一个直接证据，证明ω-6 PUFA，DGLA，通过其12-LOX氧脂素，12（S）-HETrE抑制损伤诱导的血栓形成，这强烈支持DGLA补充剂通过其调节血小板功能的潜在心脏保护益处。此外，这是12-LOX氧脂素以Gα s连接的GPCR依赖性方式调节血小板功能的第一个证据。
Dietary supplementation with polyunsaturated fatty acids (PUFAs) has been widely used for primary and secondary prevention of CVD in individuals at risk; however, the cardioprotective benefits of PUFAs remain controversial due to lack of mechanistic and in vivo evidence. We present direct evidence that an omega-6 PUFA, dihomo-γ-linolenic acid (DGLA), exhibits in vivo cardioprotection through 12-lipoxygenase (12-LOX) oxidation of DGLA to its reduced oxidized lipid form, 12(S)-HETrE, inhibiting platelet activation and thrombosis. DGLA inhibited ex vivo platelet aggregation and Rap1 activation in wild-type mice, but not in mice lacking 12-LOX expression (12-LOX−/−). Similarly, wild-type mice treated with DGLA were able to reduce thrombus growth (platelet and fibrin accumulation) following laser-induced injury of the arteriole of the cremaster muscle, but not 12-LOX−/− mice, supporting a 12-LOX requirement for mediating the inhibitory effects of DGLA on platelet-mediated thrombus formation. Platelet activation and thrombus formation were also suppressed when directly treated with 12(S)-HETrE. Importantly, two hemostatic models, tail bleeding and arteriole rupture of the cremaster muscle, showed no alteration in hemostasis following 12(S)-HETrE treatment. Finally, the mechanism for 12(S)-HETrE protection was shown to be mediated via a Gαs-linked GPCR pathway in human platelets. This study provides the first direct evidence that an omega-6 PUFA, DGLA, inhibits injury-induced thrombosis through its 12-LOX oxylipin, 12(S)-HETrE, which strongly supports the potential cardioprotective benefits of DGLA supplementation through its regulation of platelet function. Furthermore, this is the first evidence of a 12-LOX oxylipin regulating platelet function in a Gαs-linked GPCR-dependent manner.