Pivotal role of gp91(phox)-containing NADH oxidase in lipopolysaccharide-induced tumor necrosis factor-alpha expression and myocardial depression

Article

关键词: INDUCED CARDIAC-HYPERTROPHY;    NITRIC-OXIDE;    ANGIOTENSIN-II;    SUPEROXIDE-PRODUCTION;    NAD(P)H OXIDASE;    SEPTIC SHOCK;    SYNTHASE;    MICROGLIA;    HEART;    ATHEROSCLEROSIS;   

DOI  :  10.1161/01.CIR.0000160366.50210.E9

来源: SCIE

【 摘 要 】

Background - Lipopolysaccharide (LPS) induces cardiomyocyte tumor necrosis factor-alpha (TNF-alpha) production, which is responsible for myocardial depression during sepsis. The aim of this study was to investigate the role of gp91(phox)-containing NADH oxidase signaling in cardiomyocyte TNF-alpha expression and myocardial dysfunction induced by LPS. Methods and Results - In cultured mouse neonatal cardiomyocytes, LPS increased NADH oxidase ( gp91(phox) subunit) expression and superoxide generation. Deficiency of gp91(phox) or inhibition of NADH oxidase blocked TNF-alpha expression stimulated by LPS. TNF-alpha induction was also inhibited by tempol, N-acetylcysteine, or 1,3-dimethyl-2-thiourea. NADH oxidase activation by LPS increased ERK1/2 and p38 phosphorylation, and inhibition of ERK1/2 and p38 phosphorylation blocked the effect of NADH oxidase on TNF-alpha expression. Isolated mouse hearts were perfused with LPS ( 5 mu g/mL) alone or in the presence of apocynin for 1 hour. Myocardial TNF-alpha production was decreased in gp91(phox)-deficient or apocynin-treated hearts compared with those of wild type ( P < 0.05). To investigate the role of gp91(phox)-containing NADH oxidase in endotoxemia, mice were treated with LPS ( 4 mg/kg IP) for 4 and 24 hours, and their heart function was measured with a Langendorff system. Deficiency of gp91(phox) significantly attenuated LPS-induced myocardial depression ( P < 0.05). Conclusions - gp91(phox)-Containing NADH oxidase is pivotal in LPS-induced TNF-alpha expression and cardiac depression. Effects of NADH oxidase activation are mediated by ERK1/2 and p38 MAPK pathway. The present results suggest that gp91(phox)-containing NADH oxidase may represent a potential therapeutic target for myocardial dysfunction in sepsis.

【 授权许可】

Free