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J Pharmacol Exp Ther. 2018 Dec;367(3):425-432. doi: 10.1124/jpet.118.250936. Epub 2018 Oct 10.

Lipocalin-Like Prostaglandin D Synthase but Not Hemopoietic Prostaglandin D Synthase Deletion Causes Hypertension and Accelerates Thrombogenesis in Mice.

Author information

1
Department of Systems Pharmacology and Translational Therapeutics (W.-L.S., E.R., X.L., T.G., G.A.F.), Institute for Translational Medicine and Therapeutics (W.-L.S., E.R., X.L., T.G., G.R.G., G.A.F.), and Perelman School of Medicine and Department of Genetics (G.R.G.), University of Pennsylvania, Philadelphia, Pennsylvania.
2
Department of Systems Pharmacology and Translational Therapeutics (W.-L.S., E.R., X.L., T.G., G.A.F.), Institute for Translational Medicine and Therapeutics (W.-L.S., E.R., X.L., T.G., G.R.G., G.A.F.), and Perelman School of Medicine and Department of Genetics (G.R.G.), University of Pennsylvania, Philadelphia, Pennsylvania garret@upenn.edu.

Abstract

Prostaglandin (PG) D2 is formed by two distinct PGD synthases (PGDS): lipocalin-type PGDS (L-PGDS), which acts as a PGD2-producing enzyme and as extracellular lipophilic transporter, and hematopoietic PGDS (H-PGDS), a σ glutathione-S-transferase. PGD2 plays an important role in the maintenance of vascular function; however, the relative contribution of L-PGDS- and H-PGDS-dependent formation of PGD2 in this setting is unknown. To gain insight into the function played by these distinct PGDS, we assessed systemic blood pressure (BP) and thrombogenesis in L-Pgds and H-Pgds knockout (KO) mice. Deletion of L-Pgds depresses urinary PGD2 metabolite (PGDM) by ∼35%, whereas deletion of H-Pgds does so by ∼90%. Deletion of L-Pgds, but not H-Pgds, elevates BP and accelerates the thrombogenic occlusive response to a photochemical injury to the carotid artery. HQL-79, a H-PGDS inhibitor, further depresses PGDM in L-Pgds KO mice, but has no effect on BP or on the thrombogenic response. Gene expression profiling reveals that pathways relevant to vascular function are dysregulated in the aorta of L-Pgds KOs. These results indicate that the functional impact of L-Pgds deletion on vascular homeostasis may result from an autocrine effect of L-PGDS-dependent PGD2 on the vasculature and/or the L-PGDS function as lipophilic carrier protein.

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