The relationship of hydroxyeicosatetraenoic acids and F2-isoprostanes to plaque instability in human carotid atherosclerosis
The relationship of hydroxyeicosatetraenoic acids and F2-isoprostanes to plaque instability in human carotid atherosclerosis
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DOI：
10.1172/jci3985
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发表时间：
1999-02-01
影响因子：
15.9
通讯作者：
Murphy, RC
中科院分区：
文献类型：
--
作者：
Mallat, Z;Nakamura, T;Murphy, RC
有证据表明，在人类动脉粥样硬化中，氧化应激增加。然而，没有关于原位氧化应激对斑块稳定性的重要性的信息。这一信息是相关的，因为动脉粥样硬化的发病率和死亡率本质上是由不稳定斑块引起的急性缺血性综合征的后果。我们研究了从18例无症状（稳定斑块）和12例有症状（不稳定斑块）患者中通过动脉内膜切除术取出的30个颈动脉粥样硬化斑块。4条正常动脉作为对照。脂质提取和酯水解后，采用在线反相高效液相色谱-串联质谱（LC/MS/MS）分析了氧化应激的不同指标，包括羟基二十碳四烯酸（HETEs）、环氧二十碳四烯酸（EETs）、酮二十碳四烯酸（oxo-ETEs）和f -2异前列腺素。所有的测量都在严格的双盲程序中进行。我们发现动脉粥样硬化斑块中不同化合物的水平升高。HETEs的水平比eet、oxo-ETEs或f -2-异前列腺素高24倍。与无症状患者相比，有症状患者的斑块中HETEs水平显著升高（分别为1,738 +/- 274对1,002 +/- 107 pmol/mu mol脂质磷，P < 0.01），但EETs、oxo-ETEs或f -2异前列腺素水平未见升高。一种单氧花生四烯酸，9-HETE，不能从已知的酶反应中获得，是在斑块中观察到的最丰富和最重要的化合物，这表明非酶性脂质过氧化在晚期动脉粥样硬化中占主导地位，并可能促进斑块不稳定。
Evidence for increased oxidant stress has been reported in human atherosclerosis. However, no information is available about the importance of in situ oxidant stress in relation to plaque stability. This information is relevant because the morbidity and mortality of atherosclerosis are essentially the consequences of acute ischemic syndromes due to unstable plaques. We studied 30 carotid atherosclerotic plaques retrieved by endarterectomy from 18 asymptomatic (stable plaques) and 12 symptomatic patients (unstable plaques). Four normal arteries served as controls. After lipid extraction and ester hydrolysis, quantitation of different indices of oxidant stress were analyzed, including hydroxyeicosatetraenoic acids (HETEs), epoxyeicosatetraenoic acids (EETs), ketoeicosatetraenoic acids (oxo-ETEs), and F-2-isoprostanes using online reverse-phase high-performance liquid chromatography tandem mass spectrometry (LC/MS/MS). All measurements were carried out in a strictly double-blind procedure. We found elevated levels of the different compounds in atherosclerotic plaques. Levels of HETEs were 24 times higher than EETs, oxo-ETEs, or F-2-isoprostanes. Levels of HETEs, but not those of EETs, oxo-ETEs or F-2-isoprostanes, were significantly elevated in plaques retrieved from symptomatic patients compared with those retrieved from asymptomatic patients (1,738 +/- 274 vs. 1,002 +/- 107 pmol/mu mol lipid phosphorous, respectively; P < 0.01). One monooxygenated arachidonate species, 9-HETE, which cannot be derived from known enzymatic reactions, was the most abundant and significant compound observed in plaques, suggesting that nonenzymatic lipid peroxidation predominates in advanced atherosclerosis and may promote plaque instability.