Angiotensin II-induced apoptosis in rat cardiomyocyte culture: A possible role of AT1 and AT2 receptors

Ilan Goldenberg, Ehud Grossman, Kenneth A. Jacobson, Vladimir Shneyvays, Asher Shainberg

Research output: Contribution to journalArticlepeer-review

57 Scopus citations


Objectives: To investigate the mechanism of angiotensin II-induced apoptosis in cultured cardiomyocytes by determining which receptor subtype is involved, and what is the relationship between intracellular Ca2+ changes and apoptosis. Design and methods: Neonatal rat cardiomyocytes were pretreated with either the AT1 antagonist irbesartan or the AT2 antagonist PD123319 before exposure to angiotensin II. Apoptotis was evaluated using morphological technique, staining nuclei by Feulgen and Hoechst methods followed by image analysis and by in situ terminal deoxynucleotidyl transferase nick-end (TUNEL) labelling. TUNEL-positive cardiocytes were distinguished from other cells by double staining with α-sarcomeric actin. Intracellular Ca2+ changes were assessed by indo-1 fluorescence microscopy, and the effect of Ca2+ on angiotensin II-induced apoptosis was tested using the calcium channel blocker verapamil. Results: Exposure to angiotensin II (10 nmol/l) resulted in cell replication and a three-fold increase in programmed cell death (P < 0.05). Pretreatment with either irbesartan (an AT1 receptor antagonist, 100 nmol/l) or PD123319 (an AT2 receptor antagonist, 1 μmol/l) prevented the angiotensin II-induced apoptosis, indicating the presence of both AT1 and AT2 receptors on cardiomyocytes. Exposure of myocytes to angiotensin II caused an immediate and dose-dependent increase in the concentration of intracellular free Ca2+ that lasted 40-60 s. The effect was sustained in a Ca2+ free medium. Pretreatment of cells with irbesartan (100 nmol/l) and PD123319 (10 μmol/l) blocked Ca2+ elevation. Pretreatment with verapamil (10 μmol/l) prevented angiotensin II-induced apoptosis. Conclusions: Angiotensin II-induced apoptosis in rat cardiomyocytes is mediated through activation of both AT1 and AT2 receptors. The apoptotic mechanism is not related to the immediate angiotensin II-induced Ca2+ rise from intracellular stores. However, it is accompanied by cardiomyocyte proliferation and requires Ca2+ influx through L-type channel activity.

Original languageEnglish
Pages (from-to)1681-1689
Number of pages9
JournalJournal of Hypertension
Issue number9
StatePublished - Sep 2001


  • AT and AT receptors
  • Angiotensin II
  • Apoptosis
  • Ca concentration
  • Cardiomyocytes


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