NOX1/NADPH oxidase is involved in endotoxin-induced cardiomyocyte apoptosis.


The functional significance of NOX1/NADPH oxidase in the heart has not been explored due to its low expression relative to other NOX homologs identified so far. We aimed to clarify the role of NOX1/NADPH oxidase in the septic heart by utilizing mice deficient in the Nox1 gene (Nox1(-/Y)). Sepsis was induced by intraperitoneal administration of lipopolysaccharides (LPS: 25mg/kg) or cecal ligation and puncture (CLP) surgery. A marked elevation of NOX1 mRNA was demonstrated in cardiac tissue, which was accompanied by increased production of reactive oxygen species (ROS). In Nox1(-/Y) treated with LPS, cardiac dysfunction and survival were significantly improved compared with wild-type mice (Nox1(+/Y)) treated with LPS. Concomitantly, LPS-induced cardiomyocyte apoptosis and activation of caspase-3 were alleviated in Nox1(-/Y). The level of phosphorylated Akt in cardiac tissue was significantly lowered in Nox1(+/Y) but not in Nox1(-/Y) treated with LPS or that underwent CLP surgery. Increased oxidation of cysteine residues of Akt and enhanced interaction of Akt with protein phosphatase 2A (PP2A), a major phosphatase implicated in the dephosphorylation of Akt, were demonstrated in LPS-treated Nox1(+/Y). These responses to LPS were significantly attenuated in Nox1(-/Y). Taken together, ROS derived from NOX1/NADPH oxidase play a pivotal role in endotoxin-induced cardiomyocyte apoptosis by increasing oxidation of Akt and subsequent dephosphorylation by PP2A. Marked up-regulation of NOX1 may affect the risk of mortality under systemic inflammatory conditions.

DOI: 10.1016/j.freeradbiomed.2012.08.590
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@article{Matsuno2012NOX1NADPHOI, title={NOX1/NADPH oxidase is involved in endotoxin-induced cardiomyocyte apoptosis.}, author={Kuniharu Matsuno and Kazumi Iwata and Misaki Matsumoto and Masato Katsuyama and Wenhao Cui and Ayumi Murata and Hideo Nakamura and Masakazu Ibi and Kanako Ikami and Jia Nian Zhang and Satoaki Matoba and Denan Jin and Shinji Takai and Hiroaki Matsubara and Naoyuki Matsuda and Chihiro Yabe-Nishimura}, journal={Free radical biology & medicine}, year={2012}, volume={53 9}, pages={1718-28} }