title: Angiotensin II type 2 receptor stimulation: a novel option of therapeutic interference with the renin-angiotensin system in myocardial infarction?
abstract: BACKGROUND
  This study is the first to examine the effect of direct angiotensin II type 2 (AT(2)) receptor stimulation on postinfarct cardiac function with the use of the novel nonpeptide AT(2) receptor agonist compound 21 (C21).
  
  
  RESULTS
  Myocardial infarction (MI) was induced in Wistar rats by permanent ligation of the left coronary artery. Treatment with C21 (0.01, 0.03, 0.3 mg/kg per day IP) was started 24 hours after MI and was continued until euthanasia (7 days after MI). Infarct size was assessed by magnetic resonance imaging, and hemodynamic measurements were performed via transthoracic Doppler echocardiography and intracardiac Millar catheter. Cardiac tissues were analyzed for inflammation and apoptosis markers with immunoblotting and real-time reverse transcription polymerase chain reaction. C21 significantly improved systolic and diastolic ventricular function. Scar size was smallest in the C21-treated rats. In regard to underlying mechanisms, C21 diminished MI-induced Fas-ligand and caspase-3 expression in the peri-infarct zone, indicating an antiapoptotic effect. Phosphorylation of the p44/42 and p38 mitogen-activated protein kinases, both involved in the regulation of cell survival, was strongly reduced after MI but almost completely rescued by C21 treatment. Furthermore, C21 decreased MI-induced serum monocyte chemoattractant protein-1 and myeloperoxidase as well as cardiac interleukin-6, interleukin-1beta, and interleukin-2 expression, suggesting an antiinflammatory effect.
  
  
  CONCLUSIONS
  Direct AT(2) receptor stimulation may be a novel therapeutic approach to improve post-MI systolic and diastolic function by antiapoptotic and antiinflammatory mechanisms.
authors.affiliation: Center for Cardiovascular Research, Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Kaschina
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Grzesiak
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Anna
authors.initials: A
authors.lastname: Foryst-Ludwig
authors.forename: Melanie
authors.initials: M
authors.lastname: Timm
authors.forename: Franziska
authors.initials: F
authors.lastname: Rompe
authors.forename: Manuela
authors.initials: M
authors.lastname: Sommerfeld
authors.forename: U Rudolf
authors.initials: UR
authors.lastname: Kemnitz
authors.forename: Caterina
authors.initials: C
authors.lastname: Curato
authors.forename: Pawel
authors.initials: P
authors.lastname: Namsolleck
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschöpe
authors.forename: Anders
authors.initials: A
authors.lastname: Hallberg
authors.forename: Mathias
authors.initials: M
authors.lastname: Alterman
authors.forename: Thomas
authors.initials: T
authors.lastname: Hucko
authors.forename: Ingo
authors.initials: I
authors.lastname: Paetsch
authors.forename: Thore
authors.initials: T
authors.lastname: Dietrich
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schnackenburg
authors.forename: Kristof
authors.initials: K
authors.lastname: Graf
authors.forename: Björn
authors.initials: B
authors.lastname: Dahlöf
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kintscher
authors.forename: Thomas
authors.initials: T
authors.lastname: Unger
authors.forename: U Muscha
authors.initials: UM
authors.lastname: Steckelings
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003952:Diagnostic Imaging; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy; D009203:Myocardial Infarction / Q000188:drug therapy*; D051381:Rats; D017208:Rats, Wistar; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists*; D012084:Renin-Angiotensin System / Q000187:drug effects*
chemical_list: D044139:Receptor, Angiotensin, Type 2