Objectives: Recent publications suggest that the AT2 receptor (AT2R) exerts beneficial effects
after myocardial infarction (MI) in terms of infarct size as well as cardiac function.
In this study we aimed to further analyse the effect of AT2 receptors on post-MI mortality,
remodeling and cardiac function in an established mouse model of MI.
Methods:
LAD was permanently ligated in AT2R knockout (KO) and wild-type (WT) mice. In a subgroup
of WT mice the AT2R agonist CGP42112A was administered by osmotic minipumps for 7
days post-MI. We studied infarction-associated mortality within the first 7 days.
Cardiac fibrosis and vascular remodelling were histologically analysed. Cardiac function
was assessed by echocardiography and systemic blood pressure was measured using a
tip-pressure catheter. Moreover, gene expression analyses were performed.
Results: Mortality after MI was higher in mice treated with the AT2R agonist CGP42112A as
compared to mice treated with vehicle (62 vs. 40%, n=26/15, p<0.05). A trend towards increased survival of KO mice as compared to WT mice was
observed. CGP42112A induced cardiac fibrosis as evidenced by digital analysis of Picrosirius
Red-stained cardiac sections. This phenomenon was associated with an increase in cardiac
TGF-β mRNA expression in CGP42112A-treated mice (220±21% of WT TGF-β mRNA expression,
p<0.05). Neither CGP42112A treatment nor AT2R deficiency were associated with significant
changes in vascular remodeling, systemic blood pressure or cardiac function after
myocardial infarction.
Conclusions: Our data indicates that CGP42112A-induced AT2R stimulation may increase post-MI mortality
by mechanisms possibly involving TGF-β-dependent induction of cardiac fibrosis.
