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• W1984983039 abstract "Non-steroidal anti-inflammatory drugs, like selective inhibitors of the cyclo-oxygenase-2 isoform (COX-2), can upset vascular prostanoid levels in such a way that may ultimately lead to increased rates of atherothrombotic complications. This has brought cyclo-oxygenase-dependently produced vasoactive prostanoids back into the spotlight of clinical and scientific attention [1-3]. Cyclo-oxygenases cannot produce biologically active prostaglandins without the function of another class of enzyme. This is reflected by the alternative and biochemically more correct name for cyclo-oxygenases: prostaglandin H2 synthases. Cyclo-oxygenases metabolize arachidonic acid only to the cyclic endoperoxide prostaglandin H2 (PGH2) [4]. After its formation however, PGH2 must be further metabolized by a group of more specialized enzymes that are functionally coupled to cyclo-oxygenases. To date, five classes of such enzyme have been reported. The names of these enzymes, which are collectively termed prostanoid synthases, are determined by the specific products that they create. Thus, in humans, prostaglandin I2 (PGI2 or prostacyclin) synthases, thromboxane A2 (TxA2) synthases, and prostaglandin D, E, and F synthases exist [5]. Although these prostanoid synthases may be expressed specifically within a tissue, there is still much uncertainty as to whether any of these enzymes are preferentially linked to a specific cyclo-oxygenase isoform, or whether other factors, such as subcellular localization, determine their preference for either COX-1 or COX-2 [6]. This is of critical importance to the vascular prostanoid balance, as the coupling of a prostanoid synthase to a cyclo-oxygenase ultimately determines the type of biologically downstream active prostaglandin that is produced. In a few cases, there is agreement about the preferential association of a cyclo-oxygenase with a specific prostanoid synthase in vascular cells. For example, in platelets it is well-established that COX-1, which is the only cyclo-oxygenase isoform expressed in these cells, preferentially associates with TxA2 synthase [7]. In other vascular cells, where more than one cyclo-oxygenase isoform and several types of prostanoid synthases exist, there is uncertainty about the precise metabolic pathway taken by a molecule of arachidonic acid entering cyclic endoperoxide formation [5, 8]. Better understanding of the routes of prostanoid synthase metabolism is potentially of high importance, as evidenced by recent findings in mice with a deletion in the microsomal prostaglandin E2 synthase isoform 1 (mPGES1). These mice show compensatory upregulation of prostacyclin production and, when crossed with low-density lipoprotein-/- mice, exhibit delayed atherosclerosis due to this shift in prostaglandin production [9]. In the current issue of the Journal Camacho and colleagues present data that address the important question of which prostaglandin E2 (PGE2) synthases couple to which cyclo-oxygenase isoform in human vascular smooth muscle cells under both basal and inflammatory conditions [10]. Within the PGE2 synthase family, three isoforms are known to exist, one cytosolic (cPGES) and two microsomal (mPGES-1 and mPGES-2) [11]. The authors analyzed the expression and contribution of these enzymes on the synthesis of PGE2 and PGI2 using real-time polymerase chain reaction, immunoblotting techniques, and analyses of endogenous and exogenous substrate-dependent prostanoid production. They found that mPGES-1 was the major contributor to PGE2 synthesis in human vascular smooth muscle cells, and that it was the only one of the three different PGE2 synthases that was upregulated by the inflammatory conditions induced by interleukin-1β. They showed that the production of PGE2 from mPGES-1 under these conditions was dependent not only on the inducible COX-2 but also on both cyclo-oxygenase isoforms. They also observed that the time course of mPGES-1 induction following interleukin-1β treatment differed from that of COX-2. When knocking down mPGES-1 by the use of RNA interference, they observed a shift from PGE2 production to PGI2 and 6-oxo-PGF1α production. However, when either of the two cyclo-oxygenase isoforms was silenced this effect was not seen. This indicates that mPGES-1 is not preferentially linked to either one of the cyclo-oxygenase isoforms under the inflammatory conditions studied. Analyses of time course-dependent production of PGE2 and PGI2 following inhibition of COX-2, mPGES or COX-1 indirectly strengthen the concept that, at least with respect to PGI2 production, COX-2 seems to be preferentially linked to a PGI2 synthase. In this way, the authors provide data that support the concept that COX-2 is the most important cyclo-oxygenase isoform for vascular PGI2 production, a concept that has been supported by preclinical, clinical and experimental studies for some years now [12-15]. Unfortunately, in the study by Camacho and colleagues, PGI2 synthase was not knocked down in those experiments performed to assess the pathophysiological importance of this concept. Interestingly though, the time course of prostanoid synthesis following interleukin-1β treatment suggests that PGI2 synthesis appears early and may then be impeded by an induction of mPGES-1 and a downregulation of COX-2. The most intriguing finding of the studies by Camacho and colleagues might be that there is probably a competition between PGI2 synthase and mPGES-1 for PGH2, which suggests that downregulation of mPGES-1 may be a tool to upregulate, or at least preserve, levels of PGI2 synthesis. If this is the case, then inhibition of mPGES-1 may represent an interesting target for therapeutic conservation of the vasoprotective effects of PGI2. In turn, this could provide promising possibilities for the treatment of atherothrombotic and vaso-occlusive diseases. For example, as suggested by the authors, diminished PGE2 formation by vascular smooth muscle cells could be useful in the conservation of plaque stability in atherosclerotic plaques. Interestingly, other recent studies have come to a similar conclusion [9, 16]. In summary, the data presented by Camacho and colleagues draw attention to an exciting new development in our understanding of prostaglandin synthesis in dependence of prostanoid synthases and their potential situation-dependent competition for PGH2 in vascular smooth muscle cells. It would certainly be exciting to obtain more insight into the situation in other vascular wall cells, such as endothelial cells, and into the ultimate in vivo consequences of mPGES-1 inhibition. If the effects observed by Camacho and colleagues are confirmed in an in vivo situation, we might well anticipate the rise of a new therapeutic concept for vasoprotective drug therapy. The author states that he has no conflict of interest." @default.
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• W1984983039 date "2007-07-01" @default.
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• W1984983039 title "Preserving vascular prostacyclin levels by microsomal prostaglandin E2 synthase isoform 1 inhibition: a new strategy for vasoprotection?" @default.
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• W1984983039 doi "https://doi.org/10.1111/j.1538-7836.2007.02614.x" @default.
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