Sonic hedgehog carried by microparticles corrects endothelial injury through nitric oxide release.
Microparticles (MPs) are small fragments generated from the plasma membrane after cell stimulation. Among the candidate proteins harbored by MPs, we recently showed that sonic hedgehog (Shh) is present in MPs generated from activated/apoptotic human T lymphocytes [Martínez et al., Blood (2006) vol. 108, 3012-3020]. We show here that Shh carried by MPs induces nitric oxide (NO) release from endothelial cells, triggers changes in the expression and phosphorylation of enzymes related to the NO pathway, and decreases production of reactive oxygen species. When PI3-kinase and ERK signaling were specifically inhibited, the effects of MPs were reversed. In vivo injection of MPs in mice was also able to improve endothelial function by increasing NO release, and it reversed endothelial dysfunction after ischemia/reperfusion. Silencing the effects of Shh with cyclopamine, a specific inhibitor of Shh, or siRNA, an inhibitor of the Shh receptor Patched, strongly reduced production of NO elicited by MPs. Taken together, we propose that the biological message carried by MPs harboring Shh may represent a new therapeutic approach against endothelial dysfunction during acute severe endothelial injury.
Agouni
Abdelali
A
INSERM, U771, CNRS, UMR 6214, Université d'Angers, Faculté de Médecine, Rue Haute de Reculée, Angers, F-49045 France.
Mostefai
H Ahmed
HA
Porro
Chiarra
C
Carusio
Nunzia
N
Favre
Julie
J
Richard
Vincent
V
Henrion
Daniel
D
Martínez
M Carmen
MC
Andriantsitohaina
Ramaroson
R
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004578:Electron Spin Resonance Spectroscopy; D004730:Endothelium, Vascular / Q000254:growth & development* / Q000293:injuries; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008830:Microbodies / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D015534:Trans-Activators / Q000502:physiology; D014162:Transfection; D014704:Veratrum Alkaloids / Q000494:pharmacology
D004791:Enzyme Inhibitors; D053823:Hedgehog Proteins; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D015534:Trans-Activators; D014704:Veratrum Alkaloids; C509239:SHH protein, human; C496314:NOS3 protein, human; C000541:cyclopamine