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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1665.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Association Between 5-Lipoxygenase Expression and Plaque Instability in Humans

Francesco Cipollone; Andrea Mezzetti; Maria Luigia Fazia; Chiara Cuccurullo; Annalisa Iezzi; Sante Ucchino; Francesco Spigonardo; Marco Bucci; Franco Cuccurullo; Stephen M. Prescott; Diana M. Stafforini

From the Atherosclerosis Prevention Center (F. Cipollone, A.M., M.L.F., C.C., A.I., S.U., F.S., M.B., F. Cuccurullo), "G. d’Annunzio" University of Chieti, and the Clinical Research Center, "G. d’Annunzio" University Foundation, Chieti, Italy; and the Huntsman Cancer Institute (S.M.P., D.M.S.), University of Utah, Salt Lake City.

Correspondence to Francesco Cipollone, Centro Regionale per la Prevenzione dell’Aterosclerosi e Clinical Research Center, Centro per lo Studio dell’Invecchiamento (Ce.S.I.), Via Colle dell’Ara, 66013 Chieti, Italy. E-mail fcipollone{at}unich.it

Objective— The participation of 5-lipoxygenase (5-LO) in the development of atherosclerosis has been suggested by recent studies. However, a role for 5-LO as a modulator of atherosclerotic plaque instability has not been previously reported in humans. Thus, the aims of this study was to analyze the expression of 5-LO in human carotid plaques and to investigate the mechanism by which this enzyme could lead to plaque instability and rupture.

Methods and Results— We obtained atherosclerotic plaques from 60 patients undergoing carotid endarterectomy. We divided the plaques into symptomatic and symptomatic according to clinical evidence of plaque instability. Clinical evidence of plaque instability was provided by the assessment of recent ischemic symptoms attributable to the stenosis and by the presence of ipsilateral cerebral lesion(s) determined by computed tomography. Plaques were analyzed for CD68+ macrophages, CD3+ T cells, -actin+ smooth muscle cells, 5-LO, cyclooxygenase 2, matrix metalloproteinase (MMP)-2, and MMP-9 by immunohistochemical, immunoblotting, and densitometric analyses. MMP activity was assessed by zymography. Leukotriene (LT) B₄ and collagen were quantified by ELISA and Sirius red polarization, respectively. The percentage of macrophage-rich and T-cell–rich areas was larger in symptomatic compared with asymptomatic patients (25±6% versus 8±4%, P<0.0001, and 74±17 versus 18±4 cell/mm², P<0.003). 5-LO expression was higher in symptomatic compared with asymptomatic plaques (24±4% versus 6±3%, P<0.0001) and was associated with increased MMP-2 and MMP-9 expression (27±4% versus 7±3%, P<0.0001, and 29±5% versus 8±2%, P<0.0001) and activity and with decreased collagen content (6.9±2.4% versus 17.8±3.1%, P<0.01). Immunofluorescence showed that 5-LO and MMPs colocalize in activated macrophages. Notably, higher 5-LO in symptomatic plaques correlated with increased LTB₄ production (18.15±3.56 versus 11.27±3.04 ng/g tissue, P<0.0001).

Conclusions— The expression of 5-LO is elevated in symptomatic compared with asymptomatic plaques and is associated with acute ischemic syndromes, possibly through the generation of LTB₄, subsequent MMP biosynthesis, and plaque rupture.

Plaque instability involves the participation of numerous genes, the most of which are still unknown. We conducted analyses of 5-lipoxygenase expression in human carotid plaques. 5-Lipoxygenase was overexpressed in symptomatic compared with asymptomatic plaques and correlated with increased leukotriene B₄ and metalloproteinase production expression. Thus, this study indicates a potential role for 5-lipoxygenase in plaque instability.

Key Words: plaque • inflammation • lipoxygenase • leukotrienes • metalloproteinases

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