Sphingosine 1-phosphate (S1P) suppresses the collagen-induced activation of human platelets via S1P4 receptor

Onuma, Takashi; Tanabe, Kumiko; Kito, Yuko; Tsujimoto, Masanori; Uematsu, Kodai; Enomoto, Yukiko; Matsushima‐Nishiwaki, Rie; Doi, Tomoaki; Nagase, Kenji; Akamatsu, Shigeru; Tokuda, Harukuni; Ogura, Shinji; Iwama, Toru; Kozawa, Osamu; Iida, Hiroki

doi:10.1016/j.thromres.2017.06.001

Cited by 15 publications

(12 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, Fleming and co-workers were able to detect S1PR 2 , but not S1PR 1 on human platelets ( Randriamboavonjy et al, 2009 ); in this study, S1PR 2 displayed a pro-aggregating role. In another study, it has been suggested that S1P suppresses collagen-induced aggregation via S1PR 4 , but not through S1PR 1 in human platelets ( Onuma et al, 2017 ). Therefore, it seems that human platelets express S1PR 2 and S1PR 4 , with a pro- and anti-aggregant role, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…That is why blocking both S1PR 1 and S1PR 3 with VPC23019, we blocked the platelet cardioprotective effects. It is unlikely that VPC23019 interfered with platelet S1P receptors because platelets express mainly S1PR 2 and S1PR 4 ( Randriamboavonjy et al, 2009 ; Onuma et al, 2017 ) (see also below “Methodological considerations and limitations of the study ”).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Cardioprotective Properties of Human Platelets Are Lost in Uncontrolled Diabetes Mellitus: A Study in Isolated Rat Hearts

et al. 2018

View full text Add to dashboard Cite

Platelets affect myocardial damage from ischemia/reperfusion. Redox-dependent sphingosine-1-phosphate production and release are altered in diabetic platelets. Sphingosine-1-phosphate is a double-edged sword for ischemia/reperfusion injury. Therefore, we aimed to verify whether: (1) human healthy- or diabetic-platelets are cardioprotective, (2) sphingosine-1-phosphate receptors and downstream kinases play a role in platelet-induced cardioprotection, and (3) a correlation between platelet redox status and myocardial ischemia/reperfusion injury exists. Isolated rat hearts were subjected to 30-min ischemia and 1-h reperfusion. Infarct size was studied in hearts pretreated with healthy- or diabetic-platelets. Healthy-platelets were co-infused with sphingosine-1-phosphate receptor blocker, ERK-1/2 inhibitor, PI3K antagonist or PKC inhibitor to ascertain the cardioprotective mechanisms. In platelets we assessed (i) aggregation response to ADP, collagen, and arachidonic-acid, (ii) cyclooxygenase-1 levels, and (iii) AKT and ERK-phosphorylation. Platelet sphingosine-1-phosphate production and platelet levels of reactive oxygen species (ROS) were quantified and correlated to infarct size. Infarct size was reduced by about 22% in healthy-platelets pretreated hearts only. This cardioprotective effect was abrogated by either sphingosine-1-phosphate receptors or ERK/PI3K/PKC pathway blockade. Cyclooxygenase-1 levels and aggregation indices were higher in diabetic-platelets than healthy-platelets. Diabetic-platelets released less sphingosine-1-phosphate than healthy-platelets when mechanical or chemically stimulated in vitro. Yet, ROS levels were higher in diabetic-platelets and correlated with infarct size. Cardioprotective effects of healthy-platelet depend on the platelet’s capacity to activate cardiac sphingosine-1-phosphate receptors and ERK/PI3K/PKC pathways. However, diabetic-platelets release less S1P and lose cardioprotective effects. Platelet ROS levels correlate with infarct size. Whether these redox alterations are responsible for sphingosine-1-phosphate dysfunction in diabetic-platelets remains to be ascertained.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cardioprotective Properties of Human Platelets Are Lost in Uncontrolled Diabetes Mellitus: A Study in Isolated Rat Hearts

et al. 2018

View full text Add to dashboard Cite

show abstract

“…4 b, c). In contrast, activation of S1PR 4 or S1PR 5 receptors, with CYM50260 24 and A971432 35 respectively, caused strong inhibition of high PAR1-AP mediated platelet aggregation (Fig. 4 di, dii, e).…”

Section: Resultsmentioning

confidence: 92%

“…Indeed, several studies indicate that exogenous S1P can directly activate human platelets causing shape change and aggregation 18 – 21 . However, other studies reported no direct effect of S1P on platelet activation, but instead found that S1P can modulate platelet function 22 – 24 . Both enhancing as well as inhibitory effects of S1P have been reported with roles suggested of S1PR1, S1PR2 and S1PR4 13 , 17 , 22 – 25 .…”

Section: Introductionmentioning

confidence: 95%

Sphingosine-1-phosphate modulates PAR1-mediated human platelet activation in a concentration-dependent biphasic manner

Liu

Jackson

Goudswaard

et al. 2021

Sci Rep

View full text Add to dashboard Cite

Sphingosine 1-phosphate (S1P) is a bioactive signalling sphingolipid that is increased in diseases such as obesity and diabetes. S1P can modulate platelet function, however the direction of effect and S1P receptors (S1PRs) involved are controversial. Here we describe the role of S1P in regulating human platelet function and identify the receptor subtypes responsible for S1P priming. Human platelets were treated with protease-activated receptor 1 (PAR-1)-activating peptide in the presence or absence of S1P, S1PR agonists or antagonists, and sphingosine kinases inhibitors. S1P alone did not induce platelet aggregation but at low concentrations S1P enhanced PAR1-mediated platelet responses, whereas PAR1 responses were inhibited by high concentrations of S1P. This biphasic effect was mimicked by pan-S1PR agonists. Specific agonists revealed that S1PR1 receptor activation has a positive priming effect, S1PR2 and S1PR3 have no effect on platelet function, whereas S1PR4 and S1PR5 receptor activation have an inhibitory effect on PAR-1 mediated platelet function. Although platelets express both sphingosine kinase 1/2, enzymes which phosphorylate sphingosine to produce S1P, only dual and SphK2 inhibition reduced platelet function. These results support a role for SphK2-mediated S1P generation in concentration-dependent positive and negative priming of platelet function, through S1PR1 and S1PR4/5 receptors, respectively.

show abstract

“…Previous studies have demonstrated conflicting results with regard to the role of S1P in platelet aggregation. Gazit et al (17) demonstrated that reducing plasma S1P levels by knocking out both Sphk1 and Sphk2 inhibited mouse platelet aggregation, whereas Onuma et al (45) found that S1P, when added exogenously, also inhibited collagen‐induced human platelet aggregation (45). As platelet aggregation is important in hemostasis (46), we assessed whether Acer2 knockout affects the duration of bleeding as a result of a tail injury in mice.…”

Section: Discussionmentioning

confidence: 99%

Alkaline ceramidase 2 is essential for the homeostasis of plasma sphingoid bases and their phosphates

Low

et al. 2018

FASEB j.

View full text Add to dashboard Cite

Sphingosine-1-phosphate (S1P) plays important roles in cardiovascular development and immunity. S1P is abundant in plasma because erythrocytes-the major source of S1P-lack any S1P-degrading activity; however, much remains unclear about the source of the plasma S1P precursor, sphingosine (SPH), derived mainly from the hydrolysis of ceramides by the action of ceramidases that are encoded by 5 distinct genes, acid ceramidase 1 ( ASAH1)/ Asah1, ASAH2/ Asah2, alkaline ceramidase 1 ( ACER1)/ Acer1, ACER2/ Acer2, and ACER3/ Acer3, in humans/mice. Previous studies have reported that knocking out Asah1 or Asah2 failed to reduce plasma SPH and S1P levels in mice. In this study, we show that knocking out Acer1 or Acer3 also failed to reduce the blood levels of SPH or S1P in mice. In contrast, knocking out Acer2 from either whole-body or the hematopoietic lineage markedly decreased the blood levels of SPH and S1P in mice. Of interest, knocking out Acer2 from whole-body or the hematopoietic lineage also markedly decreased the levels of dihydrosphingosine (dhSPH) and dihydrosphingosine-1-phosphate (dhS1P) in blood. Taken together, these results suggest that ACER2 plays a key role in the maintenance of high plasma levels of sphingoid base-1-phosphates-S1P and dhS1P-by controlling the generation of sphingoid bases-SPH and dhSPH-in hematopoietic cells.-Li, F., Xu, R., Low, B. E., Lin, C.-L., Garcia-Barros, M., Schrandt, J., Mileva, I., Snider, A., Luo, C. K., Jiang, X.-C., Li, M.-S., Hannun, Y. A., Obeid, L. M., Wiles, M. V., Mao, C. Alkaline ceramidase 2 is essential for the homeostasis of plasma sphingoid bases and their phosphates.

show abstract

Sphingosine 1-phosphate (S1P) suppresses the collagen-induced activation of human platelets via S1P4 receptor

Cited by 15 publications

References 39 publications

Cardioprotective Properties of Human Platelets Are Lost in Uncontrolled Diabetes Mellitus: A Study in Isolated Rat Hearts

Cardioprotective Properties of Human Platelets Are Lost in Uncontrolled Diabetes Mellitus: A Study in Isolated Rat Hearts

Sphingosine-1-phosphate modulates PAR1-mediated human platelet activation in a concentration-dependent biphasic manner

Alkaline ceramidase 2 is essential for the homeostasis of plasma sphingoid bases and their phosphates

Contact Info

Product

Resources

About