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Myeloid Cell Microsomal Prostaglandin E Synthase-1 Fosters Atherogenesis in Mice

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Myeloid Cell Microsomal Prostaglandin E Synthase-1 Fosters Atherogenesis in Mice Myeloid cell microsomal prostaglandin E synthase-1 fosters atherogenesis in mice Lihong Chena, Guangrui Yanga, James Monslowb, Leslie Toddb, David P. Cormodec, Jun Tangd, Gregory R. Granta, Jonathan H. DeLonge, Soon Yew Tanga, John A. Lawsona, Ellen Pureb, and Garret A. FitzGeralda,1 aThe Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, bThe Department of Animal Biology, School of Veterinary Medicine, and cThe Department of Radiology, eDepartment of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104; and dTranslational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 Edited* by Bengt Samuelsson, Karolinska Institutet, Stockholm, Sweden, and approved March 31, 2014 (received for review January 28, 2014) Microsomal prostaglandin E synthase-1 (mPGES-1) in myeloid and Despite this attractive cardiovascular profile, mPGES-1 is vascular cells differentially regulates the response to vascular in- a complex drug target. The dominant prostanoid products of jury, reflecting distinct effects of mPGES-1–derived PGE2 in these substrate rediversion differ among cell types. For example, cell types on discrete cellular components of the vasculature. The whereas PGI2 might be augmented in vascular cells, the conse- cell selective roles of mPGES-1 in atherogenesis are unknown. Mice quence of mPGES-1 blockade in other cells might be an increase lacking mPGES-1 conditionally in myeloid cells (Mac-mPGES-1- in thromboxane (Tx)A2, a PG that promotes platelet activation, KOs), vascular smooth muscle cells (VSMC-mPGES-1-KOs), or endo- vasoconstriction, and atherogenesis (9). Even if an increase in thelial cells (EC-mPGES-1-KOs) were crossed into hyperlipidemic PGI2 afforded a desirable cardiovascular profile, it might un- low-density lipoprotein receptor-deficient animals. En face aortic dermine the analgesic efficacy of mPGES-1 inhibitors. Al- lesion analysis revealed markedly reduced atherogenesis in Mac- though the impacts of global deletion of mPGES-1 and COX-2 mPGES-1-KOs, which was concomitant with a reduction in oxidative in many mouse models of analgesia are indistinguishable stress, reflective of reduced macrophage infiltration, less lesional (12, 13), in some, PGI2 rather than PGE2 predominates (14) expression of inducible nitric oxide synthase (iNOS), and lower and thus may be the dominant mediator in certain subtypes aortic expression of NADPH oxidases and proinflammatory cyto- of human pain. Finally, the consequences of PGE2 suppression kines. Reduced oxidative stress was reflected systemically by a de- might differ between cell types. PGE2 activates four E pros- PHARMACOLOGY cline in urinary 8,12-iso-iPF2α-VI. In contrast to exaggeration of the tanoid (EP) receptors with contrasting intracellular signaling response to vascular injury, deletion of mPGES-1 in VSMCs, ECs, or and consequent biology (15, 16). Indeed, the contrasting ef- both had no detectable phenotypic impact on atherogenesis. Mac- fect of mPGES-1 deletion in myeloid vs. vascular cells on the rophage foam cell formation and cholesterol efflux, together with proliferative response to vascular injury reflects the differ- plasma cholesterol and triglycerides, were unchanged as a function ential consequences of EP activation rather than substrate of genotype. In conclusion, myeloid cell mPGES-1 promotes ath- rediversion (8). erogenesis in hyperlipidemic mice, coincident with iNOS-mediated A potentially discriminating feature among inhibitors of COX-2 oxidative stress. By contrast, mPGES-1 in vascular cells does not and mPGES-1 is their effect on atherosclerosis. Global postnatal detectably influence atherogenesis in mice. This strengthens the deletion of COX-2 accelerates atherogenesis in hyperlipidemic therapeutic rationale for targeting macrophage mPGES-1 in in- mice (17), an observation that accords with a similar effect of flammatory cardiovascular diseases. deleting the PGI2 receptor (the IP) (18, 19) and with the delayed detection of a cardiovascular hazard in randomized trials of COX-2 atherosclerosis | prostanoid Significance onsteroidal anti-inflammatory drugs (NSAIDs) reduce pain Nand inflammation by suppressing the formation of proin- Inhibitors of microsomal prostaglandin E synthase-1 (mPGES-1) flammatory prostaglandins (PGs), particularly prostaglandin are being developed as analgesics. Although global depletion of E2 (PGE2) formed by cyclooxygenase-2 (COX-2) (1). However, mPGES-1 suggests they will be less likely to confer a cardiovascular the development of NSAIDs specific for inhibition of COX-2 hazard than NSAIDs selective for inhibition of COX-2, mPGES-1– revealed a cardiovascular hazard attributable to suppression of derived PGE2 may have contrasting effects on discrete cellular components of the vasculature. mPGES-1 inhibition may result in cardioprotective PGs, especially prostacyclin (PGI2) (2). This risk appears to extend to some of the older NSAIDs, like substrate rediversion to other PG synthases, the products of which diclofenac, that also inhibit specifically COX-2 (3, 4). These differ between cell types and exert contrasting biologies. Here, myeloid cell mPGES-1, reflective of the macrophage enzyme, developments prompted interest in microsomal PGE synthase promotes atherogenesis, fostering inflammation and oxidative (mPGES)-1 as a downstream alternative drug target to COX-2 stress. By contrast, mPGES-1 in endothelial and vascular smooth (5): it is the dominant source among PGES enzymes in the muscle cells has no discernable effect. Selective targeting of biosynthesis of PGE2 (6). Unlike NSAIDs, inhibitors of mPGES-1 macrophage mPGES-1 may conserve cardiovascular benefit while would spare PGI2 from suppression. Indeed, blockade or de- avoiding adverse effects related to enzyme blockade in other letion of mPGES-1 results in accumulation of its PGH2 substrate, tissues. rendering it available for metabolism by other PG synthases, in- cluding PGI2 synthase (PGIS) (7). Author contributions: L.C., E.P., and G.A.F. designed research; L.C., G.Y., J.M., L.T., D.P.C., Consistent with these observations, we have found that whereas J.H.D., S.Y.T., and J.A.L. performed research; J.T. contributed new reagents/analytic tools; L.C., G.Y., J.M., L.T., D.P.C., G.R.G., E.P., and G.A.F. analyzed data; and L.C. and G.A.F. deletion of COX-2 in endothelial cells (ECs) and vascular smooth wrote the paper. muscle cells (VSMCs) renders mice susceptible to thrombosis and The authors declare no conflict of interest. hypertension (2), deletion of mPGES-1 in vascular cells has no *This Direct Submission article had a prearranged editor. such effect (8). Indeed, global deficiency of mPGES-1 restrains 1To whom correspondence should be addressed. E-mail: [email protected]. atherogenesis (9), the proliferative response to vascular injury (10) This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. and angiotensin-induced aortic aneurysm formation (11) in mice. 1073/pnas.1401797111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1401797111 PNAS Early Edition | 1of6 Downloaded by guest on September 24, 2021 inhibitors in patients initially selected for being at low cardio- urinary metabolites 11α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane- vascular risk (20). By contrast, global deletion of mPGES-1 1,20-dioic acid (PGE-M) and 2,3-dinor 6-keto PGF1α (PGI-M), was restrains atherogenesis in mice; in this case suppression of PGE2 not significantly affected by myeloid mPGES-1 deletion in hyper- coincides with an increase in biosynthesis of PGI2 (9). Here, we lipidemic mice (Fig. S4 A and B). Modest product rediversion to wished to segregate the effects on atherosclerosis of mPGES-1 PGD2 (PGD-M: 11,15-dioxo-9-hydroxy-2,3,4,5-tetranor-prostan-1,20- depletion in myeloid from vascular cells. Our results strengthen dioic acid) and TxA2 (Tx-M: reflected by 2,3-dinor TxB2)wasob- the rationale for targeting macrophage mPGES-1 in the treat- served in 3-mo female and 6-mo male groups, respectively (Fig. S4 C ment of inflammatory cardiovascular disease. and D). Notably, the female mice showed lower PGE-M and higher Tx-M excretion than males at both 3 mo and 6 mo (Fig. S4 A and Results D), consistent with our previous report (9). Lower PGD-M and mPGES-1 Deletion in Myeloid Cells Attenuates Atherogenesis. Start- PGI-M excretion was also observed in female mice after 6 mo HFD ing at 2 mo of age, mice of both genders were fed a high-fat diet feeding (Fig. S4 B and C). The contribution of these differences to (HFD) for 3 mo or 6 mo. Compared with either of the control the sex-dependent rate of atherogenesis in hyperlipidemic mice groups, WT1 or WT2 (Materials and Methods), the atheroscle- is unknown. rotic lesion burden was markedly reduced in Mac-mPGES-1-KOs in both male (Fig. 1A) and female mice (Fig. 1B). No difference mPGES-1 Deletion in Vascular Cells Does Not Influence Atherogenesis. was observed between WT1 and WT2; therefore for all of the In contrast to the functional importance of mPGES-1 in myeloid following experiments, we used WT1 as controls, terming them cells, deletion of mPGES-1 in vascular cells (VSMCs, ECs, or Mac-mPGES-1-WT. Weight gain and plasma total cholesterol and both) had no detectable phenotypic impact on lesion burden in triglyceride levels were not affected by myeloid mPGES-1 deletion either sex (Fig. 2 A and B). Body weight, plasma lipid levels (Fig. in either sex at any time point (Fig. S1). S5), and the urinary production of prostanoid metabolites (Fig. LysMCre mice express Cre recombinase in all myeloid cells, S6) were all unchanged by vascular mPGES-1deletion. including macrophages, neutrophils, and some dendritic cells (21). Most recently, we reported that deficiency of mPGES-1 in Morphology Consequent to Macrophage mPGES-1 Deletion in Low- macrophages results in PGE2 suppression, accompanied by an Density Lipoprotein Receptor-Deficient Mice. Genotypic distinctions increased production of PGI2 and TxB2 (8). Here we examined in morphology are often less evident at more advanced stages of the leukotriene (LT) profile.
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