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

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 PGF1α , 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 .