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

doi:10.1073/pnas.0606586103

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

*Institute for Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA 19104; and
^†Wistar Institute, 34th and Spruce Streets, Philadelphia, PA 19104

Communicated by Bengt Samuelsson, Karolinska Institutet, Stockholm, Sweden, August 3, 2006 (received for review May 3, 2006)

Abstract

Prostaglandin (PG) E₂ is formed from PGH₂ 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 11α-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 (PGI₂) 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 PGI₂ and thromboxane A₂ to varied extents. Urinary PGE-M was depressed, whereas urinary 2,3-dinor 6-keto PGF_1α, but not 2,3-dinor-TxB₂, was increased in mPGES-1^−/− LDLR^−/−s. mPGES-1-derived PGE₂ 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 PGH₂ to augment formation of PGI₂. 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 PGI₂.

Footnotes

^‡To whom correspondence should be addressed. E-mail: garret{at}spirit.gcrc.upenn.edu
Author contributions: G.A.F. designed research; M.W., A.M.Z., Y.H., and E.R. performed research; E.P. and G.A.F. analyzed data; and M.W., E.P., and G.A.F. wrote the paper.
Conflict of interest statement: G.A.F. receives financial support for investigator-initiated research from Bayer, Merck, and Boehringer Ingelheim, all of which manufacture drugs that target COXs. G.A.F. is a member of the Steering Committee of the Multinational Etoricoxib and Diclofenac Arthritis Long-Term (MEDAL) Study Program. G.A.F. also serves as a consultant for Bayer, Merck, GlaxoSmithKline, Genome Institute of the Novartis Foundation, Boehringer Ingelheim, and NicOx.
Abbreviations:

PG,

prostaglandin;

PGES,

PGE synthase;

mPGES,

microsomal PGES;

PGE-M, 11α-hydroxy-9, 15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid,

;

LDLR,

low-density lipoprotein receptor;

VSMC,

vascular smooth muscle cell;

PGI2,

prostacyclin;

PGIS,

PGI2 synthase;

Tx,

thromboxane;

TxS,

Tx synthase;

PGI-M, 2,3-dinor 6-keto PGF1α,

;

Tx-M,

2,3-dinor-TxB2;

NSAID,

nonsteroidal antiinflammatory drug;

COX,

cyclooxygenase;

EP,

E prostanoid receptor;

HFD,

high-fat diet;

TxA2,

thromboxane A2;

IP,

I prostanoid receptor;

TxS,

TxA2 synthase.
Freely available online through the PNAS open access option.