Publikationsdatenbank
The role of angiotensin AT1 and AT2 receptors in the development of apoptosis and inflammation following experimental myocardial infarction (2014)
- Art
- Hochschulschrift
- Autor
- Elkhrbash, Kamal (WE 14)
- Quelle
- Berlin: Mensch und Buch Verlag, 2014 — XV, 87 Seiten
- ISBN: 978-3-86387-560-2
- Sprache
- Englisch
- Verweise
- URL (Volltext): http://www.diss.fu-berlin.de/diss/receive/FUDISS_thesis_000000098444
- Kontakt
- Institut für Pharmakologie und Toxikologie
-
Koserstr. 20
14195 Berlin
Tel.+49 30 838 53221 Fax.+49 30 838 53112
email:pharmakologie@vetmed.fu-berlin.de - Abstract / Zusammenfassung
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Firstly, the study was designed to assess the role of the angiotensin AT1 receptor subtype 1 (AT1) and receptor subtype 2 (AT2) in apoptosis and inflammatory processes following myocardial infarction in vivo, as the data available suggests that Angiotensin II ( Ang II) induces apoptosis via AT1 and AT2 receptors.
Ang II, the most important effector peptide of the renin-angiotensin system, mediates its effects through two main receptor subtypes, namely AT1 and AT2 receptors.
Data from ex vivo studies indicates that the AT2 receptor mediates apoptotic effects.
We have previously shown that both AT1 and AT2 are expressed in adult rat cardiomyocytes and in response to myocardial infarction-induced cardiac injury.
However, it is currently unknown whether angiotensin receptors mediate apoptosis in cardiomyocytes in vivo. We have assessed the regulation of the AT1 receptor in association with the expression of apoptosis markers such as P53, Bax and Caspase-3 on day 1, day 3, day 7 and day 14 following experimental myocardial infarction in rats by Western Blot and/or immunohistochemistry. In addition, the colocalization of angiotensin receptors and apoptosis or cardiomyocyte markers were evaluated by immunofluorescence double labeling. We detected a marked upregulation of the cardiac AT1 receptor as well as P53 protein on day 7 after experimental myocardial infarction. Immunohistochemical staining revealed abundant and heterogeneous distribution of P53, Bax and Caspase-3 in the myocardium. The strongest staining of P53 was observed among injured cardiomyocytes at the border zone of the infarction. By contrast, Bax and Caspase-3 were mainly located in the area between the border zone and the necrotic lesion and the area surrounding the necrotic lesion, respectively. Also, we demonstrated a marked upregulation of cardiac AT2 receptors co-localized with ED1 positive macrophages infiltrating injured cardiomyocytes around the infarct areas.
Furthermore, our triple immunofluorescence labeling demonstrated a colocalization of AT2 receptors with IL-10 within ED1-positive macrophages infiltrating injured cardiomyocytes, suggesting a possible role of IL-10 and AT2 receptors in the inflammatory development after myocardial infarction.
Secondly, the study sought to investigate the role of AT1 and AT2 receptors in apoptosis and inflammation following myocardial infarction. We therefore investigated the influence of a specific AT1 and AT2 receptor antagonists on apoptotic markers, cytokine production and infarct size of the heart after myocardial infarction. Notably, AT1 receptor inactivation by the specific blocker valsartan treatment in rats with myocardial infarction suppressed myocardial infarction-induced upregulation of cardiac apoptosis markers including p53, Bax and Caspase-3, inhibited inflammatory reaction as indicated with reversed the increased number of ED1 macrophages infiltrating cardiomyocytes, upregulation in cardiac IL-10 and enlarged infarct area in myocardial infarction.
In contrast, no effect on apoptotic process, inflammatory reaction or enlarged infarct area in myocardial infarction was observed in rats treated with PD to block AT2 receptor.