title: Tlr4 Deficiency Protects against Cardiac Pressure Overload Induced Hyperinflammation.
abstract: Transverse aortic constriction provokes a pro-inflammatory reaction and results in cardiac hypertrophy. Endogenous ligands contribute to cardiac hypertrophy via toll-like receptor (TLR)-4 binding. A lack of TLR4 signaling diminishes hypertrophy and inflammation. Wild type mice undergoing aortic constriction respond to a lipopolysaccharide second-hit stimulus with hyperinflammation. The objective of this study was to assess whether other second-hit challenges utilizing TLR ligands provoke a comparable inflammatory reaction, and to find out whether this response is absent in TLR4 deficient mice. Assuming that cardiac stress alters the expression of pattern recognition receptors we analyzed the effects of transverse aortic constriction and second-hit virulence factor treatment on TLR expression, as well as cytokine regulation. Wild type and Tlr4-/- mice were subjected to three days of TAC and subsequently confronted with gram-positive TLR2 ligand lipoteichoic acid (LTA, 15 mg/g bodyweight) or synthetic CpG-oligodesoxynucleotide 1668 thioate (20 nmol/kg bodyweight, 30 min after D-galactosamin desensitization) signaling via TLR9. Hemodynamic measurements and organ preservation were performed 6 h after stimulation. Indeed, the study revealed a robust enhancement of LTA induced pattern recognition receptor and cytokine mRNA expression and a LTA-dependent reduction of hemodynamic pressure in TAC wild type mice. Second-Hit treatment with CpG-ODNs led to similar results. However, second-hit effects were abolished in Tlr4-/- mice. In total, these data indicate for the first time that cardiac stress increases the inflammatory response towards both, gram-negative and gram-positive, TLR ligands as well as bacterial DNA. The decrease of the inflammatory response upon TLR2 and -9 ligand challenge in TAC Tlr4-/- mice demonstrates that a lack of TLR4 signaling does not only prevent left ventricular hypertrophy but also protects the mice from a cardiac stress induced hyperinflammatory reaction.
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, University Hospital Bonn, Sigmund-Freud-Straße 25, 53105, Bonn, Germany.
authors.forename: Heidi
authors.initials: H
authors.lastname: Ehrentraut
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, University Hospital Bonn, Sigmund-Freud-Straße 25, 53105, Bonn, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Felix Ehrentraut
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, University Hospital Bonn, Sigmund-Freud-Straße 25, 53105, Bonn, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Boehm
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, University Hospital Bonn, Sigmund-Freud-Straße 25, 53105, Bonn, Germany.|Marienhaus Klinikum, Bad Neuenahr-Ahrweiler, Germany.
authors.forename: Sakina
authors.initials: S
authors.lastname: El Aissati
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, University Hospital Bonn, Sigmund-Freud-Straße 25, 53105, Bonn, Germany.|Asklepios Klinik St. Augustin, Sankt Augustin, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Foltz
authors.affiliation: Polyclinic of Orthodontics, University of Bonn, Welschnonnenstraße 17, 53111, Bonn, Germany.|Institute of Physiology II, University Hospital Bonn, Nussallee 11, 53115, Bonn, Germany.
authors.forename: Lina
authors.initials: L
authors.lastname: Goelz
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, University Hospital Bonn, Sigmund-Freud-Straße 25, 53105, Bonn, Germany.|Klinik für Orthopädie und Unfallchirurgie, HELIOS Medical Center Siegburg, Siegburg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Goertz
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, University Hospital Bonn, Sigmund-Freud-Straße 25, 53105, Bonn, Germany.|Department of Neurology, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Sied
authors.initials: S
authors.lastname: Kebir
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, University Hospital Bonn, Sigmund-Freud-Straße 25, 53105, Bonn, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Weisheit
authors.affiliation: Polyclinic of Orthodontics, University of Bonn, Welschnonnenstraße 17, 53111, Bonn, Germany.|Institute of Physiology II, University Hospital Bonn, Nussallee 11, 53115, Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Wolf
authors.affiliation: Institute of Physiology II, University Hospital Bonn, Nussallee 11, 53115, Bonn, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Meyer
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, University Hospital Bonn, Sigmund-Freud-Straße 25, 53105, Bonn, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Baumgarten
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000235:genetics* / Q000503:physiopathology; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008024:Ligands; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction; D013682:Teichoic Acids / Q000008:administration & dosage; D051195:Toll-Like Receptor 2 / Q000096:biosynthesis / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism
chemical_list: D008024:Ligands; D008070:Lipopolysaccharides; D013682:Teichoic Acids; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C009900:lipoteichoic acid