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

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.

Therapeutic Potential of Hematopoietic Prostaglandin D2 Synthase in Allergic Inflammation

“…A recently published article showed that LPGDS knock-out mice but not hPGDS knock-out mice display a cardiovascular phenotype. In the vasculature, an autocrine LPGDS-derived PGD 2 effect seems crucial to protect from hypertension and thrombogenesis [4].…”

“…Notably, in contrast to COX inhibition, specific inhibition of unfavourable pro-inflammatory PGD 2 effects and its metabolites would keep physiological functions of beneficial mediators like PGE 2 and prostacyclin intact. In mice, about 90% of the systemic biosynthesis of PGD 2 is generated by the hematopoietic PGD synthase (hPGDS)-dependent pathway and only partially through lipocalin-type PGD synthase (LPGDS) [4]. Most prostaglandins are generated by competitive enzymatic interactions, however, it has been suggested that prostaglandins may also be generated from precursor eicosanoids by non-enzymatic conversion [5], which also needs to be taken into account in a therapeutic setting.…”

Gene expression of the heat stress response in bovine peripheral white blood cells and milk somatic cells in vivo

“…In the milk somatic cells, the heat challenge induced the expression of a gene which regulates vasodilation and involved in thermoregulation. The pharmacological activities of prostaglandin D2 receptor 2 (PTGDR2) include vasodilation and bronchoconstriction [35][36][37] . Other functional roles of PTGDR2 are in thermoregulation and fever response 38 .…”

Does Beta-Trace Protein (BTP) Outperform Cystatin C as a Diagnostic Marker of Acute Kidney Injury Complicating the Early Phase of Acute Pancreatitis?

“…BTP synthesis is induced in endothelial cells under shear stress. Through prostaglandin D2 synthesis, BTP exerts vasodilating effects [52]. However, the role of BTP in endothelial dysfunction associated with systemic inflammation or sepsis remains to be elucidated.…”