Effect of Sphingosine Kinase 1 Inhibition on Blood Pressure

FASEB J. 2013 Feb;27(2):656-64. doi: 10.1096/fj.12-219014. Epub 2012 Oct 29.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Blood Pressure / physiology*
  • Celecoxib
  • Cyclooxygenase 2 / metabolism
  • Cyclooxygenase 2 Inhibitors / pharmacology
  • Dinoprostone / biosynthesis
  • Epoprostenol / biosynthesis
  • Gene Knockdown Techniques
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Hypertension / drug therapy
  • Hypertension / physiopathology
  • Intramolecular Oxidoreductases / metabolism
  • MAP Kinase Signaling System
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mitochondrial Proteins
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
  • Phosphotransferases (Alcohol Group Acceptor) / deficiency
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / physiology
  • Prostaglandin-E Synthases
  • Pyrazoles / pharmacology
  • RNA, Small Interfering / genetics
  • Sulfonamides / pharmacology

Substances

  • Cyclooxygenase 2 Inhibitors
  • Mitochondrial Proteins
  • Pyrazoles
  • RNA, Small Interfering
  • SPATA18 protein, human
  • Sulfonamides
  • Epoprostenol
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Intramolecular Oxidoreductases
  • PTGES protein, human
  • Prostaglandin-E Synthases
  • Ptges protein, mouse
  • Celecoxib
  • Dinoprostone