title: 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.
authors.forename: Konstantin A
authors.initials: KA
authors.lastname: Krychtiuk
authors.forename: Lukas
authors.initials: L
authors.lastname: Watzke
authors.forename: Christoph
authors.initials: C
authors.lastname: Kaun
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Buchberger
authors.forename: Renate
authors.initials: R
authors.lastname: Hofer-Warbinek
authors.forename: Svitlana
authors.initials: S
authors.lastname: Demyanets
authors.forename: Julia
authors.initials: J
authors.lastname: Pisoni
authors.forename: Stefan P
authors.initials: SP
authors.lastname: Kastl
authors.forename: Sabine
authors.initials: S
authors.lastname: Rauscher
authors.forename: Marion
authors.initials: M
authors.lastname: Gröger
authors.forename: Arezu
authors.initials: A
authors.lastname: Aliabadi
authors.forename: Andreas
authors.initials: A
authors.lastname: Zuckermann
authors.forename: Gerald
authors.initials: G
authors.lastname: Maurer
authors.forename: Rainer
authors.initials: R
authors.lastname: de Martin
authors.forename: Kurt
authors.initials: K
authors.lastname: Huber
authors.affiliation: Johann Wojta, PhD, Department of Internal Medicine II, Medical University of Vienna, Austria, Tel.: +43 1 4040073500, Fax: +43 1 4040073586, E-mail: johann.wojta@meduniwien.ac.at.
authors.forename: Johann
authors.initials: J
authors.lastname: Wojta
authors.forename: Walter S
authors.initials: WS
authors.lastname: Speidl
mesh_terms: D000893:Anti-Inflammatory Agents / Q000737:chemistry*; D002448:Cell Adhesion; D002478:Cells, Cultured; D003652:Decanoic Acids / Q000737:chemistry; D019040:E-Selectin / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006333:Heart Failure / Q000503:physiopathology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006835:Hydrazones / Q000737:chemistry*; D006880:Hydroxy Acids / Q000737:chemistry; D007249:Inflammation / Q000503:physiopathology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008833:Microcirculation; D008856:Microscopy, Fluorescence; D032342:Muscle Cells / Q000473:pathology; D009203:Myocardial Infarction / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D009504:Neutrophils / Q000166:cytology; D010766:Phosphorylation; D011724:Pyridazines / Q000737:chemistry*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077464:Simendan; D014665:Vasodilator Agents / Q000737:chemistry
chemical_list: D000893:Anti-Inflammatory Agents; D003652:Decanoic Acids; D019040:E-Selectin; D006835:Hydrazones; D006880:Hydroxy Acids; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D011724:Pyridazines; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D018799:Intercellular Adhesion Molecule-1; D000077464:Simendan; C052853:5-hydroxydecanoic acid
keywords: Levosimendan; cardiac myocytes; endothelial cells; granulocytes; myocardial infarction