Sphingosine 1-phosphate induces contraction of coronary artery smooth muscle cells via S1P2.
OBJECTIVE
Sphingosine 1-phosphate (Sph-1-P), a bioactive lipid derived from activated platelets, may play an important role in coronary artery spasm and hence the pathogenesis of ischemic heart diseases, since we reported that a decrease in coronary blood flow was induced by this lysophospholipid in an in vivo canine heart model [Cardiovasc. Res. 46 (2000) 119]. In this study, metabolism related to and cellular responses elicited by Sph-1-P were examined in human coronary artery smooth muscle cells (CASMCs).


RESULTS
[3H]Sphingosine (Sph), incorporated into CASMCs, was converted to [3H]Sph-1-P intracellularly, but its stimulation-dependent formation and extracellular release were not observed. Furthermore, the cell surface Sph-1-P receptors of S1P family (previously called EDG) were found to be expressed in CASMCs. Accordingly, Sph-1-P seems to act as an extracellular mediator in CASMCs. Consistent with Sph-1-P-elicited coronary vasoconstriction in vivo, Sph-1-P strongly induced CASMC contraction, which was inhibited by JTE-013, a newly-developed specific antagonist of S1P(2) (EDG-5). Furthermore, C3 exoenzyme or Y-27632 inhibited the CASMC contraction induced by Sph-1-P, indicating Rho involvement. Finally, exogenously-added [3H]Sph-1-P underwent a rapid degradation. Since lipid phosphate phosphatases, ectoenzymes capable of dephosphorylating Sph-1-P, were expressed in CASMCs, Sph-1-P may be dephosphorylated by the ectophosphatases.


CONCLUSIONS
Sph-1-P, derived from platelets and dephosphorylated on the cell surface, may induce the contraction of coronary artery smooth muscle cells through the S1P(2)/Rho signaling.
Ohmori
Tsukasa
T
Department of Laboratory Medicine, Yamanashi Medical University, Nakakoma, Japan.
Yatomi
Yutaka
Y
Osada
Makoto
M
Kazama
Fuminori
F
Takafuta
Toshiro
T
Ikeda
Hitoshi
H
Ozaki
Yukio
Y
D000209:Acute-Phase Proteins / Q000378:metabolism; D000577:Amides / Q000494:pharmacology; D001792:Blood Platelets / Q000502:physiology; D002478:Cells, Cultured; D003331:Coronary Vessels; D006801:Humans; D066298:In Vitro Techniques; D008246:Lysophospholipids; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*
D000209:Acute-Phase Proteins; D000577:Amides; C471998:JTE 013; D008246:Lysophospholipids; D011720:Pyrazoles; D011725:Pyridines; C010781:acute-phase protein rho; C108830:Y 27632; C060506:sphingosine 1-phosphate; D013110:Sphingosine