Z. Mallat et al., The relationship of hydroxyeicosatetraenoic acids and F-2-isoprostanes to plaque instability in human carotid atherosclerosis, J CLIN INV, 103(3), 1999, pp. 421-427
Evidence for increased oxidant stress has been reported in human atheroscle
rosis. However, no information is available about the importance of in situ
oxidant stress in relation to plaque stability. This information is releva
nt because the morbidity and mortality of atherosclerosis are essentially t
he consequences of acute ischemic syndromes due to unstable plaques. We stu
died 30 carotid atherosclerotic plaques retrieved by endarterectomy from 18
asymptomatic (stable plaques) and 12 symptomatic patients (unstable plaque
s). Four normal arteries served as controls. After lipid extraction and est
er hydrolysis, quantitation of different indices of oxidant stress were ana
lyzed, including hydroxyeicosatetraenoic acids (HETEs), epoxyeicosatetraeno
ic acids (EETs), ketoeicosatetraenoic acids (oxo-ETEs), and F-2-isoprostane
s using online reverse-phase high-performance liquid chromatography tandem
mass spectrometry (LC/MS/MS). All measurements were carried out in a strict
ly double-blind procedure. We found elevated levels of the different compou
nds in atherosclerotic plaques. Levels of HETEs were 24 times higher than E
ETs, 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 retri
eved from symptomatic patients compared with those retrieved from asymptoma
tic 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 abund
ant and significant compound observed in plaques, suggesting that nonenzyma
tic lipid peroxidation predominates in advanced atherosclerosis and may pro
mote plaque instability.