title: Myeloid cell microsomal prostaglandin E synthase-1 fosters atherogenesis in mice.
abstract: 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-iPF2α-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.
authors.affiliation: The Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, The Department of Animal Biology, School of Veterinary Medicine, and The Department of Radiology, Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Lihong
authors.initials: L
authors.lastname: Chen
authors.forename: Guangrui
authors.initials: G
authors.lastname: Yang
authors.forename: James
authors.initials: J
authors.lastname: Monslow
authors.forename: Leslie
authors.initials: L
authors.lastname: Todd
authors.forename: David P
authors.initials: DP
authors.lastname: Cormode
authors.forename: Jun
authors.initials: J
authors.lastname: Tang
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Grant
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: DeLong
authors.forename: Soon Yew
authors.initials: SY
authors.lastname: Tang
authors.forename: John A
authors.initials: JA
authors.lastname: Lawson
authors.forename: Ellen
authors.initials: E
authors.lastname: Pure
authors.forename: Garret A
authors.initials: GA
authors.lastname: Fitzgerald
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000201:enzymology* / Q000209:etiology* / Q000517:prevention & control; D002465:Cell Movement / Q000502:physiology; D042783:Endothelial Cells / Q000201:enzymology; D005260:Female; D006949:Hyperlipidemias / Q000201:enzymology; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008861:Microsomes / Q000201:enzymology; D022423:Myeloid Cells / Q000201:enzymology*; D032389:Myocytes, Smooth Muscle / Q000201:enzymology; D018384:Oxidative Stress; D000071876:Prostaglandin-E Synthases; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics
chemical_list: D011973:Receptors, LDL; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse
keywords: atherosclerosis; prostanoid
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