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A Pipeline to Investigate the Structures and Signaling Pathways of Sphingosine 1-Phosphate Receptors
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A Pipeline to Investigate the Structures and Signaling Pathways of Sphingosine 1-Phosphate Receptors

Published on: June 8, 2022

Effect of sphingosine kinase 1 inhibition on blood pressure

Hideki Furuya1, Masayuki Wada, Yoshiko Shimizu

  • 1University of Hawaii Cancer Center, Honolulu, HI 96813, USA.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|October 31, 2012
PubMed

Insights

Sphingosine kinase 1 (SphK1) inhibition regulates prostaglandin E2 (PGE2) production via the p38 MAPK pathway, independent of COX-2. This suggests SphK1 inhibition as a safer cancer chemoprevention strategy than COX-2 inhibitors.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Sphingosine kinase 1 (SphK1) regulates cyclooxygenase-2 (COX-2) in carcinogenesis.
  • COX-2 inhibitors can cause cardiovascular side effects by inhibiting prostacyclin (PGI(2)).
  • The role of SphK1 inhibition in blood pressure regulation is not fully understood.

Purpose of the Study:

  • To investigate the effect of SphK1 inhibition on blood pressure.
  • To elucidate the mechanism by which SphK1 influences prostaglandin production.
  • To assess the potential of SphK1 inhibition as a cancer chemoprevention strategy with reduced cardiovascular risks.

Main Methods:

  • SphK1-knockout mice and celecoxib treatment were used to study hypertension.
  • Prostaglandin E2 (PGE2) and PGI(2) production were measured in response to angiotensin II (Ang II).
  • SphK1 down-regulation using siRNA in human umbilical vein endothelial cells assessed PGE(2) production and signaling pathways.

Main Results:

  • SphK1 deficiency did not worsen Ang II-induced hypertension, unlike celecoxib.
  • SphK1-knockout mice showed reduced PGE(2) but not PGI(2) production.
  • SphK1 down-regulation decreased PGE(2) via microsomal PGE synthase-1 (mPGES-1) and the p38 MAPK pathway, independent of COX-2.

Conclusions:

  • SphK1 regulates PGE(2) production through mPGES-1 and the p38 MAPK pathway in endothelial cells.
  • SphK1 inhibition offers a potential cancer chemoprevention approach without the cardiovascular risks associated with COX-2 inhibitors.
  • Targeting SphK1 may provide a safer alternative for managing cancer and associated inflammatory pathways.

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