title: Cardiovascular Consequences of Prostanoid I Receptor Deletion in Microsomal Prostaglandin E Synthase-1-Deficient Hyperlipidemic Mice.
abstract: Inhibitors of cyclooxygenase-2 alleviate pain and reduce fever and inflammation by suppressing the biosynthesis of prostacyclin (PGI2) and prostaglandin E2. However, suppression of these prostaglandins, particularly PGI2, by cyclooxygenase-2 inhibition or deletion of its I prostanoid receptor also predisposes to accelerated atherogenesis and thrombosis in mice. By contrast, deletion of microsomal prostaglandin E synthase 1 (mPGES-1) confers analgesia, attenuates atherogenesis, and fails to accelerate thrombogenesis, while suppressing prostaglandin E2, but increasing biosynthesis of PGI2.
  
  
  
  To address the cardioprotective contribution of PGI2, we generated mice lacking the I prostanoid receptor together with mPges-1 on a hyperlipidemic background (low-density lipoprotein receptor knockouts).
  
  
  
  mPges-1 depletion modestly increased thrombogenesis, but this response was markedly further augmented by coincident deletion of the I prostanoid receptor (n=10-18). By contrast, deletion of the I prostanoid receptor had no effect on the attenuation of atherogenesis by mPGES-1 deletion in the low-density lipoprotein receptor knockout mice (n=17-21).
  
  
  
  Although suppression of prostaglandin E2 accounts for the protective effect of mPGES-1 deletion in atherosclerosis, augmentation of PGI2 is the dominant contributor to its favorable thrombogenic profile. The divergent effects on these prostaglandins suggest that inhibitors of mPGES-1 may be less likely to cause cardiovascular adverse effects than nonsteroidal anti-inflammatory drugs specific for inhibition of cyclooxygenase-2.
authors.affiliation: From Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, Department of Systems Pharmacology and Translational Therapeutics (S.Y.T., J.M., L.T., S.-C.P., L.C., E.P., G.A.F.); Department of Animal Biology, School of Veterinary Medicine (S.Y.T., G.R.G., J.L.); and Department of Genetics, University of Pennsylvania, Philadelphia (J.M.).
authors.forename: Soon Yew
authors.initials: SY
authors.lastname: Tang
authors.affiliation: From Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, Department of Systems Pharmacology and Translational Therapeutics (S.Y.T., J.M., L.T., S.-C.P., L.C., E.P., G.A.F.); Department of Animal Biology, School of Veterinary Medicine (S.Y.T., G.R.G., J.L.); and Department of Genetics, University of Pennsylvania, Philadelphia (J.M.).
authors.forename: James
authors.initials: J
authors.lastname: Monslow
authors.affiliation: From Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, Department of Systems Pharmacology and Translational Therapeutics (S.Y.T., J.M., L.T., S.-C.P., L.C., E.P., G.A.F.); Department of Animal Biology, School of Veterinary Medicine (S.Y.T., G.R.G., J.L.); and Department of Genetics, University of Pennsylvania, Philadelphia (J.M.).
authors.forename: Gregory
authors.initials: G
authors.lastname: R Grant
authors.affiliation: From Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, Department of Systems Pharmacology and Translational Therapeutics (S.Y.T., J.M., L.T., S.-C.P., L.C., E.P., G.A.F.); Department of Animal Biology, School of Veterinary Medicine (S.Y.T., G.R.G., J.L.); and Department of Genetics, University of Pennsylvania, Philadelphia (J.M.).
authors.forename: Leslie
authors.initials: L
authors.lastname: Todd
authors.affiliation: From Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, Department of Systems Pharmacology and Translational Therapeutics (S.Y.T., J.M., L.T., S.-C.P., L.C., E.P., G.A.F.); Department of Animal Biology, School of Veterinary Medicine (S.Y.T., G.R.G., J.L.); and Department of Genetics, University of Pennsylvania, Philadelphia (J.M.).
authors.forename: Sven-Christian
authors.initials: SC
authors.lastname: Pawelzik
authors.affiliation: From Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, Department of Systems Pharmacology and Translational Therapeutics (S.Y.T., J.M., L.T., S.-C.P., L.C., E.P., G.A.F.); Department of Animal Biology, School of Veterinary Medicine (S.Y.T., G.R.G., J.L.); and Department of Genetics, University of Pennsylvania, Philadelphia (J.M.).
authors.forename: Lihong
authors.initials: L
authors.lastname: Chen
authors.affiliation: From Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, Department of Systems Pharmacology and Translational Therapeutics (S.Y.T., J.M., L.T., S.-C.P., L.C., E.P., G.A.F.); Department of Animal Biology, School of Veterinary Medicine (S.Y.T., G.R.G., J.L.); and Department of Genetics, University of Pennsylvania, Philadelphia (J.M.).
authors.forename: John
authors.initials: J
authors.lastname: Lawson
authors.affiliation: From Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, Department of Systems Pharmacology and Translational Therapeutics (S.Y.T., J.M., L.T., S.-C.P., L.C., E.P., G.A.F.); Department of Animal Biology, School of Veterinary Medicine (S.Y.T., G.R.G., J.L.); and Department of Genetics, University of Pennsylvania, Philadelphia (J.M.).
authors.forename: Ellen
authors.initials: E
authors.lastname: Puré
authors.affiliation: From Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, Department of Systems Pharmacology and Translational Therapeutics (S.Y.T., J.M., L.T., S.-C.P., L.C., E.P., G.A.F.); Department of Animal Biology, School of Veterinary Medicine (S.Y.T., G.R.G., J.L.); and Department of Genetics, University of Pennsylvania, Philadelphia (J.M.). garret@upenn.edu.
authors.forename: Garret A
authors.initials: GA
authors.lastname: FitzGerald
mesh_terms: D000818:Animals; D001018:Aortic Diseases / Q000201:enzymology / Q000235:genetics; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics; D017536:Carotid Artery, Common / Q000528:radiation effects; D016893:Carotid Stenosis / Q000209:etiology; D011464:Epoprostenol / Q000502:physiology*; D006949:Hyperlipidemias / Q000201:enzymology / Q000235:genetics*; D007834:Lasers / Q000009:adverse effects; D051379:Mice; D018345:Mice, Knockout; D008861:Microsomes / Q000201:enzymology; D020641:Polymorphism, Single Nucleotide; D000071876:Prostaglandin-E Synthases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D044006:Receptors, Epoprostenol; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D011982:Receptors, Prostaglandin / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
chemical_list: C491910:Ptgir protein, mouse; D044006:Receptors, Epoprostenol; D011973:Receptors, LDL; D011982:Receptors, Prostaglandin; D011464:Epoprostenol; D000071876:Prostaglandin-E Synthases
keywords: atherosclerosis; cyclooxygenase 2; dinoprostone; epoprostenol; prostaglandin-E synthase; thrombosis