title: Deletion of microsomal prostaglandin E synthase-1 augments prostacyclin and retards atherogenesis.
abstract: Prostaglandin (PG) E(2) is formed from PGH(2) by a series of PGE synthase (PGES) enzymes. Microsomal PGES-1(-/-) (mPGES-1(-/-)) mice were crossed into low-density lipoprotein receptor knockout (LDLR(-/-)) mice to generate mPGES-1(-/-) LDLR(-/-)s. Urinary 11alpha-hydroxy-9, 15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M) was depressed by mPGES-1 deletion. Vascular mPGES-1 was augmented during atherogenesis in LDLR(-/-)s. Deletion of mPGES-1 reduced plaque burden in fat-fed LDLR(-/-)s but did not alter blood pressure. mPGES-1(-/-) LDLR(-/-) plaques were enriched with fibrillar collagens relative to LDLR(-/-), which also contained small and intermediate-sized collagens. Macrophage foam cells were depleted in mPGES-1(-/-) LDLR(-/-) lesions, whereas the total areas rich in vascular smooth muscle cell (VSMC) and matrix were unaltered. mPGES-1 deletion augmented expression of both prostacyclin (PGI(2)) and thromboxane (Tx) synthases in endothelial cells, and VSMCs expressing PGI synthase were enriched in mPGES-1(-/-) LDLR(-/-) lesions. Stimulation of mPGES-1(-/-) VSMC and macrophages with bacterial LPS increased PGI(2) and thromboxane A(2) to varied extents. Urinary PGE-M was depressed, whereas urinary 2,3-dinor 6-keto PGF(1alpha), but not 2,3-dinor-TxB(2), was increased in mPGES-1(-/-) LDLR(-/-)s. mPGES-1-derived PGE(2) accelerates atherogenesis in LDLR(-/-) mice. Disruption of this enzyme retards atherogenesis, without an attendant impact on blood pressure. This may reflect, in part, rediversion of accumulated PGH(2) to augment formation of PGI(2). Inhibitors of mPGES-1 may be less likely than those selective for cyclooxygenase 2 to result in cardiovascular complications because of a divergent impact on the biosynthesis of PGI(2).
authors.affiliation: Institute for Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA 19104, USA.
authors.forename: Miao
authors.initials: M
authors.lastname: Wang
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Zukas
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Hui
authors.forename: Emanuela
authors.initials: E
authors.lastname: Ricciotti
authors.forename: Ellen
authors.initials: E
authors.lastname: Puré
authors.forename: Garret A
authors.initials: GA
authors.lastname: FitzGerald
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D050197:Atherosclerosis / Q000473:pathology*; D015232:Dinoprostone / Q000096:biosynthesis; D011464:Epoprostenol / Q000096:biosynthesis*; D005260:Female; D017353:Gene Deletion; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008861:Microsomes / Q000201:enzymology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000473:pathology; D000071876:Prostaglandin-E Synthases; D011973:Receptors, LDL / Q000172:deficiency; D013928:Thromboxane A2 / Q000096:biosynthesis
chemical_list: D011973:Receptors, LDL; D013928:Thromboxane A2; D011464:Epoprostenol; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone