期刊
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
卷 1820, 期 12, 页码 2095-2104出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbagen.2012.08.014
关键词
NO synthases; Inflammation; NF-kappa B; H9c2; Aminobenzyl acetamidine-derivative
资金
- Universita' degli Studi G. D'Annunzio di Chieti e Pescara (Italy)
Background: 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. Methods: 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-kappa B) were assayed. Results: 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 -IKK alpha/beta-I kappa B alpha. simultaneously to the inactivation of the PI3K/Akt pathway. The compounds acted as an anti-inflammatory modulator. Conclusion: 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-IKK alpha/beta-I kappa Ba, 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. General significance: This study delineates the underlying mechanisms of opposite NOSs expression in H9c2 cells stimulated with LPS. (c) 2012 Published by Elsevier B.V.
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