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VOL. 74 (4) PROSTANOIDS ACTIONS IN CARDIOVASCULAR...

COX-1 but not with COX-2 (10, 54). However, PGIS expression can be
induced together with COX-2 in endothelial cells by hemodynamic shear
stress or by oxidized low density lipoproteins (oxLDLs) leading to PGI2
production (60, 61). Moreover, in healthy individuals COX-2 specific
inhibitors reduce PGI2 metabolites in urine without affecting TXA2
metabolites (62). This suggests that COX-2 is a major source of PGI2 in
the human cardiovascular system and plays a role under physiological
conditions. The predominant coupling of PGI2 to COX-2 suggests that
COX-2 specific inhibitor could be prothrombotic, since anti-aggregatory
PGI2 circulating levels within would be reduced. This has been proposed
to explain the putative associations between COX-2 inhibitors and the
development of cardiovascular complications (63, 64). In contrast to TP
deficient mice, IP knockout mice have normal blood pressure and develop
normally without suffering from spontaneous thrombosis. However, after
endothelial damage they show an enhanced thrombotic response
compared to control littermates (65), indicating that PGI2 does play a
major role only in response to stress and not in the basal systemic
circulation. Mice lacking IP have enhanced vascular smooth cell
proliferation and platelet activation in response to vascular injury likely
caused by enhanced TXA2/PGI2 ratio (51). Simultaneous deletion of the
TP and the IP abrogated both increased responses (51). Selective
inhibition, knockout, mutation or deletion of COX-2 or IP has been
shown to accelerate thrombogenesis. These responses were attenuated by
COX-1 knock down (66). IP KO mice also show vascular hyperplasia and
increased vascular remodeling (67) as well as cardiac hypertrophy and
fibrosis (68). Taken together those results indicate that PGI2 regulates the
cardiovascular activity of TXA2 and further support the hypothesis that
cardiovascular homeostasis is resulting from the balance between these
two eicosanoids.

ROLE OF PROSTANOIDS IN ATHEROSCLEROSIS

Atherosclerosis is one of the most important diseases of the
developed countries and can be considered as a multifactorial
in?ammatory disease triggered by high levels of cholesterol in serum

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