Key result
Levosimendan and dextrosimendan dose-dependently decreased NO production, iNOS expression, and NF-κB-mediated transcription in cells exposed to inflammatory stimuli.
Why the study?
Do levosimendan and dextrosimendan reduce NO production and iNOS expression in macrophages and fibroblasts exposed to inflammatory stimuli?
Do levosimendan and dextrosimendan reduce NO production and iNOS expression in macrophages and fibroblasts exposed to inflammatory stimuli?
Levosimendan and dextrosimendan downregulate NF-kappaB-dependent transcription and decrease iNOS expression and NO production, providing a potential mechanism for their beneficial clinical effects in heart failure and sepsis.
Hypothesis-generating for anti-inflammatory effects in heart failure or sepsis; leaves open clinical translation from cellular data.
BACKGROUND AND PURPOSE: Levosimendan is used in the treatment of decompensated heart failure. It increases the contractility of the myocardium by sensitizing troponin C to calcium. In addition, levosimendan has been reported to have beneficial effects in experimental models of septic shock. Because heart failure and sepsis have been associated with excessive nitric oxide (NO) production through inducible NOS (iNOS), we investigated the effects of the simendans on NO production and iNOS expression and on generation of pro-inflammatory cytokines. EXPERIMENTAL APPROACH: Macrophages and fibroblasts were exposed to inflammatory stimuli to induce iNOS expression. Proteins were measured by western blot and mRNA expression was determined by quantitative RT-PCR. Promoter activity and nuclear factor-kappaB (NF-kappaB) and the gamma-activated site (GAS; binding site for signal transducer and activator of transcription 1; STAT1)-mediated transcription were investigated using luciferase reporter constructs. Cytokines tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were measured by ELISA. KEY RESULTS: Levosimendan and dextrosimendan decreased NO production in a dose-dependent manner in cells exposed to inflammatory stimuli. The simendans decreased iNOS protein and mRNA expression but did not affect iNOS mRNA decay. These compounds decreased iNOS promoter activity and inhibited NF-kappaB-mediated transcription but not that mediated by STAT1/GAS. The simendans reduced IL-6 production slightly but they had no effect on TNF-alpha synthesis. CONCLUSIONS AND IMPLICATIONS: The simendans downregulated NF-kappaB-dependent transcription and decreased iNOS promoter activity, iNOS expression and NO production. These mechanisms may contribute to their beneficial clinical effects.
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Sareila et al. (2008) studied Inflammation (in vitro model for heart failure and sepsis). Levosimendan and dextrosimendan was evaluated on NO production, iNOS expression, and NF-kappaB-mediated transcription. Levosimendan and dextrosimendan dose-dependently decreased NO production, iNOS expression, and NF-κB-mediated transcription in cells exposed to inflammatory stimuli.
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