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M. FRESNO Y COLS. AN. R. ACAD. NAC. FARM

following vascular injury (83). Genetic deletion of the IP receptor, both in
the LDRL and in the ApoE KO mice models, aggravated atherogenesis
(72, 84). As platelets are though to contribute to the development and
progression of atherosclerosis in the late phase, PGI2 may likely suppress
lesion formation by limiting platelet deposition. Those mice exhibited a
significant acceleration in atherogenesis with enhanced platelet activation
and increased rolling of leukocytes on the vessel walls. Those results
indicate that TXA2 promotes whereas PGI2 prevents the initiation and
progression of atherogenesis by modulating platelet activation and
leukocyte-endothelial cell interaction.

In addition to PGI2 and TXA2, other PGs, such as PGE2 and PGD2,
could also play an important role in the pathophysiology of
atherosclerosis. In this regard, vasoconstrictor responses to PGE2 are
greatly increased in atherosclerosis (85) and PGE2 may also promote
angiogenesis (3). Moreover, inducible mPGES-1 has been detected in
activated macrophages in atherosclerotic lesions where it colocalizes with
COX-2 both in mice and humans (73). Disruption of this enzyme in mice
reduced foam cell formation and atherosclerosis in fat-fed LDLR-/- mice.
mPGES-1 deletion augmented both PGIS and TXS expression in
endothelial cells (86). On the other hand, COX-2 derived PGs as PGD2
may possess anti-inflammatory and anti-atherosclerotic properties in such
a way that the balance between PGDS and PGES has been shown to be a
major determinant of atherosclerotic plaque instability (87).

PHARMACOLOGICAL IMPLICATIONS

Based on the hypothesis that atherosclerosis is an inflammatory
disease, it was proposed that COX inhibition by NSAIDs, and in
particular selective inhibition of COX-2 by the Coxibs family of NSAIDs,
might have protective and even anti-atherogenic effects. However,
clinical studies have indicated that there is an increased risk of
atherothrombosis in individuals taking these drugs in such a way that
some of them as Rofecoxib have been recently withdrawn from the
market (88-91). These undesirable effects of COX-2 selective inhibitors
have been explained by the TXA2/PGI2 balance theory by which selective

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