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(Circulation. 2008;118:2523-2532.)
© 2008 American Heart Association, Inc.

Coronary Heart Disease

Angiotensin II Type 2 Receptor Stimulation

A Novel Option of Therapeutic Interference With the Renin-Angiotensin System in Myocardial Infarction?

Elena Kaschina, MD^*; Aleksandra Grzesiak, MD^*; Jun Li, MD; Anna Foryst-Ludwig, PhD; Melanie Timm, MTA; Franziska Rompe, MSc; Manuela Sommerfeld, MTA; U. Rudolf Kemnitz, MTA; Caterina Curato, MSc; Pawel Namsolleck, MSc; Carsten Tschöpe, MD, PhD; Anders Hallberg, PhD; Mathias Alterman, PhD; Thomas Hucko, MD; Ingo Paetsch, MD, PhD; Thore Dietrich, PhD; Bernhard Schnackenburg, PhD; Kristof Graf, MD, PhD; Björn Dahlöf, MD, PhD; Ulrich Kintscher, MD, PhD; Thomas Unger, MD, PhD^*; U. Muscha Steckelings, MD^*

From the Center for Cardiovascular Research, Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Berlin, Germany (E.K., A.G., J.L., A.F.-L., M.T., F.R., M.S., U.R.K., C.C., P.N., U.K., T.U., U.M.S.); Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany (C.T.); Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University, Uppsala, Sweden (A.H., M.A.); Deutsches Herzzentrum Berlin, Klinik für Innere Medizin—Kardiologie, Berlin, Germany (T.H., I.P., T.D., K.G.); Philips Clinical Science, Hamburg, Germany (B.S.); and Sahlgrenska University Hospital/Östra, Göteborg, Sweden (B.D.).

Correspondence to Dr Thomas Unger, Center for Cardiovascular Research, Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Hessische Strasse 3–4, 10115 Berlin, Germany. E-mail thomas.unger{at}charite.de

Received April 9, 2008; accepted September 12, 2008.

Background— This study is the first to examine the effect of direct angiotensin II type 2 (AT₂) receptor stimulation on postinfarct cardiac function with the use of the novel nonpeptide AT₂ receptor agonist compound 21 (C21).

Methods and 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-1β, and interleukin-2 expression, suggesting an antiinflammatory effect.

Conclusions— Direct AT₂ receptor stimulation may be a novel therapeutic approach to improve post-MI systolic and diastolic function by antiapoptotic and antiinflammatory mechanisms.

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CLINICAL PERSPECTIVE

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Clinical Summaries
Circulation 2008 118: 2485-2487. [Extract] [Full Text]

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