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Levosimendan exerts anti-inflammatory effects on cardiac myocytes and endothelial cells in vitro.

Abstract
Levosimendan is a positive inotropic drug for the treatment of acute decompensated heart failure (HF). Clinical trials showed that levosimendan was particularly effective in HF due to myocardial infarction. Myocardial necrosis induces a strong inflammatory response, involving chemoattractants guiding polymorphonuclear neutrophils (PMN) into the infarcted myocardial tissue. Our aim was to examine whether levosimendan exhibits anti-inflammatory effects on human adult cardiac myocytes (HACM) and human heart microvascular endothelial cells (HHMEC). Cardiac myocytes and endothelial cells were stimulated with interleukin-1β (IL)-1β (200 U/ml) and treated with levosimendan (0.1-10 µM) for 2-48 hours. IL-1β strongly induced expression of IL-6 and IL-8 in HACM and E-selectin and intercellular adhesion molecule-1 (ICAM-1) in HHMEC and human umbilical vein endothelial cells (HUVEC). Treatment with levosimendan strongly attenuated IL-1β-induced expression of IL-6 and IL-8 in HACM as well as E-selectin and ICAM-1 in ECs. Levosimendan treatment further reduced adhesion of PMN to activated endothelial cells under both static and flow conditions by approximately 50 %. Incubation with 5-hydroxydecanoic acid, a selective blocker of mitochondrial ATP-dependent potassium channels, partly abolished the above seen anti-inflammatory effects. Additionally, levosimendan strongly diminished IL-1β-induced reactive oxygen species and nuclear factor-κB (NF-κB) activity through inhibition of S536 phosphorylation. In conclusion, levosimendan exhibits anti-inflammatory effects on cardiac myocytes and endothelial cells in vitro. These findings could explain, at least in part, the beneficial effects of levosimendan after myocardial infarction.
AuthorsKonstantin A Krychtiuk, Lukas Watzke, Christoph Kaun, Elisabeth Buchberger, Renate Hofer-Warbinek, Svitlana Demyanets, Julia Pisoni, Stefan P Kastl, Sabine Rauscher, Marion Gröger, Arezu Aliabadi, Andreas Zuckermann, Gerald Maurer, Rainer de Martin, Kurt Huber, Johann Wojta, Walter S Speidl
JournalThrombosis and haemostasis (Thromb Haemost) Vol. 113 Issue 2 Pg. 350-62 (Feb 2015) ISSN: 2567-689X [Electronic] Germany
PMID25273157 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Anti-Inflammatory Agents
  • Decanoic Acids
  • E-Selectin
  • Hydrazones
  • Hydroxy Acids
  • Interleukin-1beta
  • Interleukin-6
  • Interleukin-8
  • NF-kappa B
  • Pyridazines
  • Reactive Oxygen Species
  • Vasodilator Agents
  • Intercellular Adhesion Molecule-1
  • Simendan
  • 5-hydroxydecanoic acid
Topics
  • Anti-Inflammatory Agents (chemistry)
  • Cell Adhesion
  • Cells, Cultured
  • Decanoic Acids (chemistry)
  • E-Selectin (metabolism)
  • Enzyme-Linked Immunosorbent Assay
  • Heart Failure (physiopathology)
  • Human Umbilical Vein Endothelial Cells (drug effects, metabolism)
  • Humans
  • Hydrazones (chemistry)
  • Hydroxy Acids (chemistry)
  • Inflammation (physiopathology)
  • Intercellular Adhesion Molecule-1 (metabolism)
  • Interleukin-1beta (metabolism)
  • Interleukin-6 (metabolism)
  • Interleukin-8 (metabolism)
  • Microcirculation
  • Microscopy, Fluorescence
  • Muscle Cells (pathology)
  • Myocardial Infarction (physiopathology)
  • Myocytes, Cardiac (cytology, drug effects)
  • NF-kappa B (metabolism)
  • Necrosis
  • Neutrophils (cytology)
  • Phosphorylation
  • Pyridazines (chemistry)
  • Reactive Oxygen Species (metabolism)
  • Simendan
  • Vasodilator Agents (chemistry)

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