Effect of sphingosine kinase 1 inhibition on blood pressure

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.

S1P Signaling and De Novo Biosynthesis in Blood Pressure Homeostasis

“…Interestingly, S1P administration reverted the hypotension induced by histamine in Sphk1 2/2 mice, suggesting SPHK1 as a positive regulator of MABP. In line with this evidence, the lack of SPHK1 attenuated the elevation of BP in response to the acute (Furuya et al, 2013;Wilson et al, 2015) and chronic (Wilson et al, 2015) administration of AngII. A positive role of SPHK1 in BP homeostasis has also been shown in an animal model of potassium-induced cardiac arrest with resuscitation (Gorshkova et al, 2013).…”

“…A positive role of SPHK1 in BP homeostasis has also been shown in an animal model of potassium-induced cardiac arrest with resuscitation (Gorshkova et al, 2013). Interestingly, Furuya et al (2013) also demonstrated that the absence of Sphk2 prolonged the acute hypertension induced by AngII, suggesting that SPHK2 protects from high BP.…”

“…In physiologic conditions, MABP was not altered by the loss of Sphk1 2/2 or Sphk2 2/2 (Furuya et al, 2013;Gorshkova et al, 2013), or the overexpression of SPHK1 (Takuwa et al, 2010). In a model of histamine-induced hypotension, Olivera et al (2010) showed that Sphk1 2/2 mice, but not Sphk2 2/2 mice, were significantly more hypotensive than WT mice.…”

Sphingosine kinase 1 (Sphk1) negatively regulates platelet activation and thrombus formation

“…Sphingosine kinase 1 disrupts COX-2 signaling and positively regulates microsomal PGE synthase 1 (mPGES-1) (14). Since sphingosine kinase 1 increases PGE 2 and decreases TXA 2 , it modifies platelet activity by influencing the balance between PGE 2 and TXA 2 concentration and production.…”

“…While both isoforms are expressed in platelets, sphingosine kinase 1 seems to be the most important isoform in platelets (48). Furthermore, spingosine kinase 1 is able to disrupt the cyooxygenase-2 (COX-2) signaling, thus decreasing PGI 2 and increasing thromboxane formation (14).…”