Deletion of microsomal prostaglandin E synthase-1 augments prostacyclin and retards atherogenesis - PubMed (original) (raw)

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

Miao Wang et al. Proc Natl Acad Sci U S A. 2006.

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).

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Conflict of interest statement

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.

Figures

Fig. 1.

Fig. 1.

mPGES-1 is induced during atherogenesis. (A) mPGES-1 expression was examined by real-time PCR in aorta from mice fed chow diet and after 6-mo HFD. Data shown are the mean ± SEM from duplicate determinations with n = 3 per group. ∗, P < 0.05. (B) mPGES-1 expression in an atherosclerotic lesion. Lesions from LDLR−/− and mPGES-1−/− LDLR−/− mice were stained with blocking peptide-preabsorbed mPGES-1 antibody (Left) and/or the antibody alone (Center and Right). (Scale bar, 100 μm.)

Fig. 2.

Fig. 2.

mPGES-1 deletion retards atherogenesis in LDLR−/− mice. (A) The extent of atherosclerosis, represented by the ratio of lesion area to total aortic area, was quantified by en face analysis of aortae from mice treated with a HFD for 3 or 6 mo (Upper). Representative en face graphs are shown (Lower), with each vertically matched to the corresponding data set in Upper. (B) Box-and-whiskers graph revealing the crosssectional analysis of aortic root samples from female mice after 6 mo on HFD, measuring total lesion area across the aortic root as detailed in Materials and Methods (Upper). A representative crosssection from each group is shown (Lower), vertically aligned with the corresponding data in Upper. (Scale bar, 500 μm.) ∗, P < 0.05; ∗∗, P < 0.01; n = 10–15 per group.

Fig. 3.

Fig. 3.

Effects of mPGES-1 deletion on lesional morphology in LDLR−/− mice. Smooth muscle cells and macrophages were stained by antibodies against α-smooth muscle actin (α-SMA; A Left) and CD11b (A Center), respectively. Macrophages were depleted in the mPGES-1−/− LDLR−/−s. Collagen content was stained by sirius red (A Right). Note the fibrillar collagen content of the mPGES-1−/− LDLR−/− neointima. All stainings in A were performed on one lesion of each genotype. Another set of α-SMA staining is shown in B. [Scale bar, 200 μm (A) and 100 μm (B).] Quantitative analysis (C) of macrophage-foam cells reveals a significant decrease in the ratio of foam cell area to lesion area. ∗, P = 0.02.

Fig. 4.

Fig. 4.

Biosynthesis of PGI2 and TxA2 during atherogenesis. Systemic production of PGI2 and TxA2 was examined by measuring their urinary metabolites, PGI-M and Tx-M. Both increased during atherogenesis in the LDLR−/− mice and substrate redirection to PGI2 (A), but not TxA2 (B), is observed in response to mPGES-1 deletion. This is sustained during the study period in hyperlipidemic mice. Data shown are from females. ∗, P < 0.05; ∗∗, P < 0.01; ∗∗∗, P < 0.001; n = 11–16 per group.

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