gms | German Medical Science

Previous studies have revealed that cardiac angiotensin receptors, including AT1 and AT2 subtypes, are upregulated after myocardial infarction (MI). In addition, we have previously shown that the number of cardiomyocytes that express the AT1 and AT2 receptor mRNA is not increased in the noninfarcted myocardium (remote from the infarction). The cell sources of these upregulated angiotensin receptors and their potential relevance in myocardial ischemia-induced apoptosis and inflammation are not yet defined. Cardiac apoptosis and inflammation were characterized by evaluating cardiac expression of apoptotic markers such as p53, Bax and caspase-3 and anti-inflammatory cytokine IL-10, respectively, using Western Blot / immunohistochemistry analysis. Seven days after experimental MI in rats, cardiac p53, Bax, caspase-3 and IL-10 were significantly upregulated. Multiple immunofluorescence labeling demonstrated that both increased AT1 receptor and p53 were colocalized in cardiomyocytes (alpha-sarcomeric actin+) in the border-zone of the infarction whereas AT2 receptor and IL-10 were mainly co-expressed in infiltrated macrophages (ED1+) in the area between the border-zone and necrosis. Blocking AT1 receptors via valsartan dramatically suppressed the cardiac expression of apoptotic markers including p53, Bax and caspase-3 but enhanced the expression of IL-10, whereas blocking AT2 receptors via PD 123319 failed to influence the expression of theses apoptotic markers, but PD 123319 significantly attenuated the cardiac expression of IL-10. These results suggest a divergent role of AT1 and AT2 receptors in myocardial ischemia-induced apoptosis and inflammation. AT1 receptors may initiate cardiomyocyte apoptosis by inducing p53-triggered apoptotic cascade whereas AT2 receptors may exert an anti-inflammatory effect by mediating cardiac IL-10 expression in infiltrated macrophages.