The impact of microsomal prostaglandin e synthase 1 on blood pressure is determined by genetic background

Abstract

Prostaglandin (PG)E2 has multiple actions that may affect blood pressure. It is synthesized from arachidonic acid by the sequential actions of phospholipases, cyclooxygenases, and PGE synthases. Although microsomal PGE synthase (mPGES)1 is the only genetically verified PGE synthase, results of previous studies examining the consequences of mPGES1 deficiency on blood pressure (BP) are conflicting. To determine whether genetic background modifies the impact of mPGES1l on BP, we generated mPGES1/ mice on 2 distinct inbred backgrounds, DBA/1lacJ and 129/SvEv. On the DBA/1 background, baseline BP was similar between wild-type (WT) and mPGES1/ mice. By contrast, on the 129 background, baseline BPs were significantly higher in mPGES1l animals than WT controls. During angiotensin II infusion, the DBA/1 mPGES1l and WT mice developed mild hypertension of similar magnitude, whereas 129-mPGES1l mice developed more severe hypertension than WT controls. DBA/1 animals developed only minimal albuminuria in response to angiotensin II infusion. By contrast, WT 129 mice had significantly higher levels of albumin excretion than WT DBA/1 and the extent of albuminuria was further augmented in 129 mPGES1l animals. In WT mice of both strains, the increase in urinary excretion of PGE2 with angiotensin II was attenuated in mPGES1l animals. Urinary excretion of thromboxane was unaffected by angiotensin II in the DBA/1 lines but increased more than 4-fold in 129 mPGES1l mice. These data indicate that genetic background significantly modifies the BP response to mPGES1 deficiency. Exaggerated production of thromboxane may contribute to the robust hypertension and albuminuria in 129 mPGES1-deficient mice. © 2010 American Heart Association. All rights reserved.