Angiotensin II type 2 receptor stimulation: a novel option of therapeutic interference with the renin-angiotensin system in myocardial infarction?
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.
Kaschina
Elena
E
Center for Cardiovascular Research, Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Grzesiak
Aleksandra
A
Li
Jun
J
Foryst-Ludwig
Anna
A
Timm
Melanie
M
Rompe
Franziska
F
Sommerfeld
Manuela
M
Kemnitz
U Rudolf
UR
Curato
Caterina
C
Namsolleck
Pawel
P
Tschöpe
Carsten
C
Hallberg
Anders
A
Alterman
Mathias
M
Hucko
Thomas
T
Paetsch
Ingo
I
Dietrich
Thore
T
Schnackenburg
Bernhard
B
Graf
Kristof
K
Dahlöf
Björn
B
Kintscher
Ulrich
U
Unger
Thomas
T
Steckelings
U Muscha
UM
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*
D044139:Receptor, Angiotensin, Type 2