P564Levosimendan exhibits anti-inflammatory effects on human cardiac myocytes and endothelial cells in vitro

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Abstract

Purpose

Levosimendan is a positive inotrope drug for the treatment of acute decompensated heart failure (HF). In clinical trials, levosimendan was shown to be effective in particular in HF due to acute myocardial infarction (AMI) and it has been demonstrated that levosimendan reduces infarct size in animal models. Myocardial cell necrosis leads to neutrophil recruitment and an inflammatory reaction. The aim of the present study was to examine whether levosimendan has anti-inflammatory effects on human adult cardiac myocytes (HACM) and human umbilical vein endothelial cells (HUVECs).

Methods

Primary HACM were isolated from ventricular tissue from explanted human hearts of patients undergoing heart transplantation. HACM were treated with tumor necrosis factor-α (TNF-α) (2000U/ml) or interleukin-1 (IL-1) (200U/ml) and incubated with or without levosimendan (10 µM). Specific mRNA levels of IL-6 and IL-8 were determined by real-time PCR. HUVEC were treated with IL-1 for 4h and expression of E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) was measured by flow cytometry.

Results

Treatment with TNF and IL-1 significantly increased mRNA levels of IL-6 (3-fold and 6-fold, respectively; p < 0.01) and IL-8 (10-fold and 20-fold, respectively; p < 0.01) in HACM. Co-treatment with levosimendan reduced such TNF-α-induced IL-6 and IL-8 mRNA levels significantly by 40% and 50%, respectively (p < 0.05). IL-1 induced IL-6 and IL-8 mRNA levels were both significantly reduced by 50% (p < 0.01) when co-treated with levosimendan. HUVECs treated with IL-1 showed a significantly higher expression of E-selectin, ICAM-1 and VCAM-1 after 4h (12-fold, 30-fold and 15-fold expression, as compared to control, respectively; p < 0.001 for all). Preincubation with levosimendan significantly down regulated the IL-1-induced expression of E-selectin and ICAM-1 by 50% and 25%, as compared to control, respectively; p < 0.05).

Conclusions

Levosimendan down regulates TNF-α- and IL-1-induced expression of inflammatory cytokines and adhesion molecules in cardiac myocytes and in endothelial cells, respectively. This may explain, at least in part, cardioprotective effects of levosimendan.

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