Sphingosine-1-phosphate activates the AKT pathway to protect small intestines from radiation-induced endothelial apoptosis.
A previous in vitro study showed that sphingosine-1-phosphate (S1P), a ceramide antagonist, preserved endothelial cells in culture from radiation-induced apoptosis. We proposed to validate the role of S1P in tissue radioprotection by inhibiting acute gastrointestinal (GI) syndrome induced by endothelial cell apoptosis after high dose of radiation. Retro-orbital S1P was injected in mice exposed to 15 Gy, a dose-inducing GI syndrome within 10 days. Overall survival and apoptosis on intestines sections were studied. Intestinal cell type targeted by S1P and early molecular survival pathways were researched using irradiated in vitro cell models and in vivo mouse models. We showed that retro-orbital S1P injection before irradiation prevented GI syndrome by inhibiting endothelium collapse. We defined endothelium as a specific therapeutic target because only these cells and not intestinal epithelial cells, or B and T lymphocytes, were protected. Pharmacologic approaches using AKT inhibitor and pertussis toxin established that S1P affords endothelial cell protection in vitro and in vivo through a mechanism involving AKT and 7-pass transmembrane receptors coupled to Gi proteins. Our results provide strong pharmacologic and mechanistic proofs that S1P protects endothelial cells against acute radiation enteropathy.
Inserm UMR892-Centre de Recherche en Cancérologie Nantes-Angers, Nantes, France.
Stéphanie
S
Bonnaud
Colin
C
Niaudet
François
F
Legoux
Isabelle
I
Corre
Gregory
G
Delpon
Xavier
X
Saulquin
Zvi
Z
Fuks
Marie-Hélène
MH
Gaugler
Richard
R
Kolesnick
François
F
Paris
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D015153:Blotting, Western; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D002460:Cell Line; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D006801:Humans; D007150:Immunohistochemistry; D007421:Intestine, Small / Q000166:cytology / Q000187:drug effects* / Q000528:radiation effects; D008221:Lymphoid Tissue / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D008246:Lysophospholipids / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011833:Radiation Injuries, Experimental / Q000188:drug therapy; D015398:Signal Transduction / Q000187:drug effects*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013577:Syndrome
D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D051057:Proto-Oncogene Proteins c-akt; D013110:Sphingosine