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Cipollone, F. et al.

Cipollone, Fazia, Iezzi, Ciabattoni, Pini, Cuccurullo, Ucchino, Spigonardo, De Luca, Prontera, Chiarelli, Cuccurullo, Mezzetti,

Balance between PGD synthase and PGE synthase is a major determinant of atherosclerotic plaque instability in humans.

OBJECTIVE: Inducible cyclooxygenase ( COX-2) catalyzes the first step in prostanoid biosynthesis and is considered a proinflammatory enzyme. COX-2 and type 1 inducible PGE synthase (mPGES-1) have a role in metalloproteinase (MMP) release leading to plaque rupture. In contrast, lipocalin-type PGD synthase (L-PGDS) has been shown to exert antiinflammatory actions. Thus, in this study we investigated whether a shift from a PGDS-oriented to a PGES-oriented profile in arachidonate metabolism leads to inflammatory activation in rupture-prone plaque macrophages. METHODS AND RESULTS: Atherosclerotic plaques were obtained from 60 patients who underwent carotid endarterectomy, symptomatic (n=30) and asymptomatic (n=30) according to evidence of recent transient ischemic attack or stroke. Plaques were analyzed for COX-2, mPGES-1, L-PGDS, PPARgamma, IkappaBalpha, NF-kappaB, and MMP-9 by immunocytochemistry, Western blot, reverse-transcriptase polymerase chain reaction, enzyme immunoassay, and zymography. Prostaglandin E2 (PGE2) pathway was significantly prevalent in symptomatic plaques, whereas PGD2 pathway was overexpressed in asymptomatic ones, associated with NF-kappaB inactivation and MMP-9 suppression. In vitro COX-2 inhibition in monocytes was associated with reduced MMP-9 release only when PGD2 pathway overcame PGE2 pathway. CONCLUSIONS: These results suggest that COX-2 may have proinflammatory and antiinflammatory properties as a function of expression of downstream PGH2 isomerases, and that the switch from L-PGDS to mPGES-1 in plaque macrophages is associated with cerebral ischemic syndromes, possibly through MMP-induced plaque rupture.[1]

References

Balance between PGD synthase and PGE synthase is a major determinant of atherosclerotic plaque instability in humans. Cipollone, F., Fazia, M., Iezzi, A., Ciabattoni, G., Pini, B., Cuccurullo, C., Ucchino, S., Spigonardo, F., De Luca, M., Prontera, C., Chiarelli, F., Cuccurullo, F., Mezzetti, A. Arterioscler. Thromb. Vasc. Biol. (2004) [Pubmed]

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