Agouni Abdelali, Mostefai H Ahmed, Porro Chiarra, Carusio Nunzia, Favre Julie, Richard Vincent, Henrion Daniel, Martínez M Carmen, Andriantsitohaina Ramaroson
INSERM, U771, CNRS, UMR 6214, Université d'Angers, Faculté de Médecine, Rue Haute de Reculée, Angers, F-49045 France.
FASEB J. 2007 Sep;21(11):2735-41. doi: 10.1096/fj.07-8079com. Epub 2007 Apr 11.
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.
微粒（MPs）是细胞受刺激后从质膜产生的小碎片。在MPs携带的候选蛋白中，我们最近发现，音猬因子（Shh）存在于活化/凋亡的人T淋巴细胞产生的MPs中[Martínez等人，《血液》（2006年）第108卷，3012 - 3020页]。我们在此表明，MPs携带的Shh可诱导内皮细胞释放一氧化氮（NO），引发与NO途径相关的酶的表达和磷酸化变化，并减少活性氧的产生。当PI3激酶和ERK信号被特异性抑制时，MPs的作用被逆转。在小鼠体内注射MPs也能够通过增加NO释放来改善内皮功能，并且能逆转缺血/再灌注后的内皮功能障碍。用环杷明（一种Shh的特异性抑制剂）或siRNA（一种Shh受体Patched的抑制剂）使Shh的作用沉默，可强烈降低MPs引发的NO产生。综上所述，我们认为携带Shh的MPs所携带的生物学信息可能代表了一种针对急性严重内皮损伤期间内皮功能障碍的新治疗方法。
