Novel aminobenzyl-acetamidine derivative modulate the differential regulation of NOSs in LPS induced inflammatory response: role of PI3K/Akt pathway.

Antonia Patruno, Sara Franceschelli, Mirko Pesce, Cristina Maccallini, Marialuigia Fantacuzzi, Lorenza Speranza, Alessio Ferrone, Maria Anna De Lutiis, Emanuela Ricciotti, Rosa Amoroso, Mario Felaco

Department of Medicine and Aging Science, University G. d'Annunzio, Chieti, Italy. antoniapatruno@unich.it

Biochimica et biophysica acta 2012 Dec

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Previous reports suggest that NO may contribute to the pathophysiology of septic shock. Recently, we have synthesized and characterized a series of benzyl- and dibenzyl derivative of N-(3-aminobenzyl)acetamidine, a potent and selective inhibitor of iNOS, in vitro assay. We evaluated the molecular mechanisms by which these compounds are involved in the regulation of NOSs expression. H9c2 cells were stimulated with lipopolysaccharide (LPS) in the presence or absence of acetamidine-derivative. The NOSs mRNA and protein, and activation of signaling pathways (Akt and NF-κB) were assayed. The induction of endotoxic shock in H9c2 with LPS caused an increase of inducible NOS and a down-regulation of constitutive NOS. The molecular mechanism involved in the modulation of NOSs expression in H9c2 cells upon LPS stimulation resulted in the modification of the redox state responsible for NF-kB nuclear translocation via NIK -IKKα/β-IkBα, simultaneously to the inactivation of the PI3K/Akt pathway. The compounds acted as an anti-inflammatory modulator. These results suggest that LPS regulates the opposite NOS expression in H9c2 cells by modifying the redox state of these cells responsible for the NF-kB nuclear translocation via NIK-IKKα/β-IkBα, simultaneous to the inactivation of the PI3K/Akt pathway. The new molecule acts as an anti-inflammatory modulator in LPS-induced inflammation in H9c2 cells by the restoration of eNOS and nNOS expressions, mechanistically involving the PI3K/Akt pathway. This study delineates the underlying mechanisms of opposite NOSs expression in H9c2 cells stimulated with LPS. Copyright © 2012. Published by Elsevier B.V.

Citation

Antonia Patruno, Sara Franceschelli, Mirko Pesce, Cristina Maccallini, Marialuigia Fantacuzzi, Lorenza Speranza, Alessio Ferrone, Maria Anna De Lutiis, Emanuela Ricciotti, Rosa Amoroso, Mario Felaco. Novel aminobenzyl-acetamidine derivative modulate the differential regulation of NOSs in LPS induced inflammatory response: role of PI3K/Akt pathway. Biochimica et biophysica acta. 2012 Dec;1820(12):2095-104