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Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):14507-12. Epub 2006 Sep 14.

Deletion of microsomal prostaglandin E synthase-1 augments prostacyclin and retards atherogenesis.

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  • 1Institute for Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA 19104, USA.

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).

PMID:
16973753
[PubMed - indexed for MEDLINE]
PMCID:
PMC1566188
Free PMC Article

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