Myeloid cell microsomal prostaglandin E synthase-1 fosters atherogenesis in mice

Microsomal prostaglandin E synthase-1 (mPGES-1) in myeloid and vascular cells differentially regulates the response to vascular injury, reflecting distinct effects of mPGES-1–derived PGE₂ in these cell types on discrete cellular components of the vasculature. The cell selective roles of mPGES-1 in atherogenesis are unknown. Mice lacking mPGES-1 conditionally in myeloid cells (Mac-mPGES-1-KOs), vascular smooth muscle cells (VSMC-mPGES-1-KOs), or endothelial cells (EC-mPGES-1-KOs) were crossed into hyperlipidemic low-density lipoprotein receptor-deficient animals. En face aortic lesion analysis revealed markedly reduced atherogenesis in Mac-mPGES-1-KOs, which was concomitant with a reduction in oxidative stress, reflective of reduced macrophage infiltration, less lesional expression of inducible nitric oxide synthase (iNOS), and lower aortic expression of NADPH oxidases and proinflammatory cytokines. Reduced oxidative stress was reflected systemically by a decline in urinary 8,12-iso-iPF_2α-VI. In contrast to exaggeration of the response to vascular injury, deletion of mPGES-1 in VSMCs, ECs, or both had no detectable phenotypic impact on atherogenesis. Macrophage foam cell formation and cholesterol efflux, together with plasma cholesterol and triglycerides, were unchanged as a function of genotype. In conclusion, myeloid cell mPGES-1 promotes atherogenesis in hyperlipidemic mice, coincident with iNOS-mediated oxidative stress. By contrast, mPGES-1 in vascular cells does not detectably influence atherogenesis in mice. This strengthens the therapeutic rationale for targeting macrophage mPGES-1 in inflammatory cardiovascular diseases.Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce pain and inflammation by suppressing the formation of proinflammatory prostaglandins (PGs), particularly prostaglandin E₂ (PGE₂) formed by cyclooxygenase-2 (COX-2) (1). However, the development of NSAIDs specific for inhibition of COX-2 revealed a cardiovascular hazard attributable to suppression of cardioprotective PGs, especially prostacyclin (PGI₂) (2). This risk appears to extend to some of the older NSAIDs, like diclofenac, that also inhibit specifically COX-2 (3, 4). These developments prompted interest in microsomal PGE synthase (mPGES)-1 as a downstream alternative drug target to COX-2 (5): it is the dominant source among PGES enzymes in the biosynthesis of PGE₂ (6). Unlike NSAIDs, inhibitors of mPGES-1 would spare PGI₂ from suppression. Indeed, blockade or deletion of mPGES-1 results in accumulation of its PGH₂ substrate, rendering it available for metabolism by other PG synthases, including PGI₂ synthase (PGIS) (7).Consistent with these observations, we have found that whereas deletion of COX-2 in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) renders mice susceptible to thrombosis and hypertension (2), deletion of mPGES-1 in vascular cells has no such effect (8). Indeed, global deficiency of mPGES-1 restrains atherogenesis (9), the proliferative response to vascular injury (10) and angiotensin-induced aortic aneurysm formation (11) in mice.Despite this attractive cardiovascular profile, mPGES-1 is a complex drug target. The dominant prostanoid products of substrate rediversion differ among cell types. For example, whereas PGI₂ might be augmented in vascular cells, the consequence of mPGES-1 blockade in other cells might be an increase in thromboxane (Tx)A₂, a PG that promotes platelet activation, vasoconstriction, and atherogenesis (9). Even if an increase in PGI₂ afforded a desirable cardiovascular profile, it might undermine the analgesic efficacy of mPGES-1 inhibitors. Although the impacts of global deletion of mPGES-1 and COX-2 in many mouse models of analgesia are indistinguishable (12, 13), in some, PGI₂ rather than PGE₂ predominates (14) and thus may be the dominant mediator in certain subtypes of human pain. Finally, the consequences of PGE₂ suppression might differ between cell types. PGE₂ activates four E prostanoid (EP) receptors with contrasting intracellular signaling and consequent biology (15, 16). Indeed, the contrasting effect of mPGES-1 deletion in myeloid vs. vascular cells on the proliferative response to vascular injury reflects the differential consequences of EP activation rather than substrate rediversion (8).A potentially discriminating feature among inhibitors of COX-2 and mPGES-1 is their effect on atherosclerosis. Global postnatal deletion of COX-2 accelerates atherogenesis in hyperlipidemic mice (17), an observation that accords with a similar effect of deleting the PGI₂ receptor (the IP) (18, 19) and with the delayed detection of a cardiovascular hazard in randomized trials of COX-2 inhibitors in patients initially selected for being at low cardiovascular risk (20). By contrast, global deletion of mPGES-1 restrains atherogenesis in mice; in this case suppression of PGE₂ coincides with an increase in biosynthesis of PGI₂ (9). Here, we wished to segregate the effects on atherosclerosis of mPGES-1 depletion in myeloid from vascular cells. Our results strengthen the rationale for targeting macrophage mPGES-1 in the treatment of inflammatory cardiovascular disease.