12-Hydroxyeicosatetraenoic acid 是唯一一种在脑缺血情况下会增加的酶促 HETE。

Mikhail Y. Golovko, Drew R. Seeger, Brennon Schofield, Derek Besch, Peddanna Kotha, Anahita Mansouripour, Shahram Solaymani-Mohammadi, Svetlana A. Golovko
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引用次数: 0

摘要

脑缺血时,羟基二十碳四烯酸(HETE)会急剧增加,并严重影响缺血后的恢复。然而,人们对缺血时 HETE 增加的确切机制及其来源知之甚少。HETE 可能是通过依赖于脂氧合酶(LOX)的合成从头生成的,并可能酯化成脂质储存库,也可能是通过酯化花生四烯酸(20:4n6)的自由基氧化非酶促生成的。由于通过 LOX 合成的 HETE 具有立体特异性,因此通过手性分析可以将酶池与非酶池分开。在本研究中,我们分析了缺血 30 秒、2 分钟和 10 分钟时游离的 HETE 立体异构体。与之前的报告一致,我们发现脑缺血 10 分钟后,所有分析的 HETE 都会显著、逐渐增加,这可能是由于酯化池的释放所致。5-HETE、8-HETE和15-HETE的R/S比值与外消旋标准混合物没有差异,表明它们是非酶源的,这与我们研究中用作阳性对照的炎症组织相反。然而,12(S)-HETE 是缺血状态下最主要的同工酶,表明 90% 的 12-HETE 是酶促产生的。这些数据首次证明,12-LOX 是缺血条件下酶促形成诱导性 HETE 池的主要 LOX 同工酶。我们还证实了准确定量 HETE 需要高能聚焦微波照射(MW)使酶失活,并验证了其在手性 HETE 分析中的应用。总之,我们的数据表明,12-LOX 和 HETE 释放酶是调节脑缺血时 HETE 水平的有希望的靶点。
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12-Hydroxyeicosatetraenoic acid is the only enzymatically produced HETE increased under brain ischemia.

Hydroxyeicosatetraenoic acids (HETE) are dramatically increased under brain ischemia and significantly affect post-ischemic recovery. However, the exact mechanism of HETE increase and their origin under ischemia are poorly understood. HETE might be produced de novo through lipoxygenase (LOX) -dependent synthesis with possible esterification into a lipid storage pool, or non-enzymatically through free radical oxidation of esterified arachidonic acid (20:4n6). Because HETE synthesized through LOX exhibit stereospecificity, chiral analysis allows separation of enzymatic from non-enzymatic pools. In the present study, we analyzed free HETE stereoisomers at 30 sec, 2 min, and 10 min of ischemia. Consistent with previous reports, we demonstrated a significant, gradual increase in all analyzed HETE over 10 min of brain ischemia, likely attributed to release of the esterified pool. The R/S ratio for 5-HETE, 8-HETE, and 15-HETE was not different from a racemic standard mix, indicating their non-enzymatic origin, which was in opposition to the inflamed tissue used as a positive control in our study. However, 12(S)-HETE was the predominant isoform under ischemia, indicating that ∼90 % of 12-HETE are produced enzymatically. These data demonstrate, for the first time, that 12-LOX is the major LOX isoform responsible for the enzymatic formation of the inducible HETE pool under ischemia. We also confirmed the requirement for enzyme inactivation with high-energy focused microwave irradiation (MW) for accurate HETE quantification and validated its application for chiral HETE analysis. Together, our data suggest that 12-LOX and HETE-releasing enzymes are promising targets for HETE level modulation upon brain ischemia.

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来源期刊
Prostaglandins, leukotrienes, and essential fatty acids
Prostaglandins, leukotrienes, and essential fatty acids Clinical Biochemistry, Endocrinology, Diabetes and Metabolism
CiteScore
5.30
自引率
0.00%
发文量
0
审稿时长
64 days
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