Accumulating evidence suggests that
sphingosine kinase 1 (SphK1) plays a key role in
carcinogenesis by regulating
cyclooxygenase-2 (COX-2) expression. Recent clinical studies have revealed that
COX-2 inhibitors cause adverse cardiovascular side effects, likely due to inhibition of
prostacyclin (PGI(2)). In this work, we investigated the roles of SphK1 inhibition on blood pressure (BP). The results show that lack of SphK1 expression did not exacerbate
angiotensin II (Ang II)-induced acute
hypertension, whereas
celecoxib, a
COX-2 inhibitor, augmented and sustained higher BP in mice. Interestingly, SphK1-knockout mice inhibited
prostaglandin E(2) (
PGE(2)) but not PGI(2) production in response to Ang II, whereas
celecoxib blocked both
PGE(2) and PGI(2) production. Mechanistically, SphK1 down-regulation by
siRNA in human umbilical vein endothelial cells decreased
cytokine-induced
PGE(2) production primarily through inhibition of microsomal
PGE synthase-1 (mPGES-1), not COX-2. SphK1 down-regulation also decreased MKK6 expression, which phosphorylates and activates
P38 MAPK, which, in turn, regulates early growth response-1 (Egr-1), a
transcription factor of mPGES-1. Together, these data indicate that SphK1 regulates
PGE(2) production by mPGES-1 expression via the
p38 MAPK pathway, independent of COX-2 signaling, in endothelial cells, suggesting that SphK1 inhibition may be a promising strategy for
cancer chemoprevention with lack of the adverse cardiovascular side effects associated with
coxibs.