title: Priming with synthetic oligonucleotides attenuates pressure overload-induced inflammation and cardiac hypertrophy in mice.
abstract: OBJECTIVE
  Inflammation and Toll-like receptor (TLR) signalling have been linked to the development of cardiac hypertrophy following transverse aortic constriction (TAC). In the present study, we investigated whether pre-treatment with the synthetic TLR9 ligands 1668-thioate or 1612-thioate modulates the progression of TAC-induced cardiac inflammation and hypertrophy.
  
  
  RESULTS
  C57BL/6N-mice were pre-treated with 1668-thioate, 1612-thioate (0.25 nmol/g, i.p.), or phosphate-buffered saline 16 h prior to TAC or sham surgery. Heart-weight/body-weight ratio (HW/BW), cardiomyocyte cell size, cellular macrophage accumulation, myofibroblast differentiation, and collagen deposition were investigated for up to 28 days. Cardiac function was monitored using a pressure-volume catheter and M-mode echocardiography. Inflammatory gene expression in the heart was analysed via gene array, while the time course of mRNA expression of key inflammatory mediators was assessed via RT-qPCR. TAC increased the HW/BW ratio and cardiomyocyte cell size and induced macrophage accumulation, myofibroblast differentiation, and collagen deposition. These changes were accompanied by cardiac inflammation and a significant loss of left ventricular function. Pre-treatment with cytosine-phosphate-guanine (CpG)-containing 1668-thioate attenuated the inflammatory response, the progression of cardiac hypertrophy, and cardiac remodelling, which resulted in a prolonged preservation of left ventricular function. These changes were induced to a smaller extent by the use of the non-CG-containing oligodeoxynucleotide 1612-thioate.
  
  
  CONCLUSIONS
  Pre-treatment with 1668-thioate attenuated cardiac hypertrophy following pressure overload, possibly by modifying the hypertrophy-induced inflammatory response, thereby reducing cardiac growth and fibrosis as well as delaying loss of cardiac function.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine,  University Hospital Bonn, Sigmund-Freud-Strasse 25, Bonn D-53105,  Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Velten
authors.forename: Georg D
authors.initials: GD
authors.lastname: Duerr
authors.forename: Thilo
authors.initials: T
authors.lastname: Pessies
authors.forename: Julia
authors.initials: J
authors.lastname: Schild
authors.forename: Ralph
authors.initials: R
authors.lastname: Lohner
authors.forename: Jan
authors.initials: J
authors.lastname: Mersmann
authors.forename: Oliver
authors.initials: O
authors.lastname: Dewald
authors.forename: Kai
authors.initials: K
authors.lastname: Zacharowski
authors.forename: Sven
authors.initials: S
authors.lastname: Klaschik
authors.forename: Tobias
authors.initials: T
authors.lastname: Hilbert
authors.forename: Andreas
authors.initials: A
authors.lastname: Hoeft
authors.forename: Georg
authors.initials: G
authors.lastname: Baumgarten
authors.forename: Rainer
authors.initials: R
authors.lastname: Meyer
authors.forename: Olaf
authors.initials: O
authors.lastname: Boehm
authors.forename: Pascal
authors.initials: P
authors.lastname: Knuefermann
mesh_terms: D000818:Animals; D006328:Cardiac Catheterization; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D002316:Cardiotonic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000378:metabolism; D054407:Chemokine CCL4 / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism; D008024:Ligands; D008262:Macrophage Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009205:Myocarditis / Q000000981:diagnostic imaging / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D009206:Myocardium / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013997:Time Factors; D051217:Toll-Like Receptor 9 / Q000819:agonists* / Q000378:metabolism; D014463:Ultrasonography; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: C408982:CPG-oligonucleotide; D002316:Cardiotonic Agents; C491768:Ccl2 protein, mouse; C496535:Ccl4 protein, mouse; D018932:Chemokine CCL2; D054407:Chemokine CCL4; D018836:Inflammation Mediators; D008024:Ligands; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D003094:Collagen