Candesartan prevents angiotensin II-induced facilitation of hypoxic neuronal damage through PKC delta inhibition

K Utsugisawa, Y Nagane, Taiju Utsugisawa, D Obara, Y Terayama

Research output: Contribution to journalArticlepeer-review

2 Citations (SciVal)

Abstract

To investigate the role of protein kinase C delta (PKC delta) in angiotensin II-induced facilitation mechanisms of hypoxic neuronal damage and whether candesartan, an AT1 receptor antagonist, can suppress these mechanisms, we performed in vitro experiments which were free from vascular components using PC12 cells under hypoxic (12 h)/reoxygenation (0-48 h) conditions. Angiotensin II apparently increased the basal expression level of PKC delta phosphorylated at Ser(643) before hypoxia, promoted the cleavage of PKC delta to its catalytic fragment, and fostered the progression of DNA fragmentation after hypoxia. Candesartan inhibited both phosphorylation and cleavage of PKC delta and suppressed the angiotensin II-induced facilitation of DNA fragmentation under hypoxic/reoxygenation conditions. However, PD123319, an AT2 receptor antagonist, influenced neither PKC delta nor the angiotensin II-induced facilitation of DNA fragmentation. Furthermore, in PC12 cells expressing the ATP-binding mutant of PKC delta (PKC delta(K376R)) acting as a dominant-negative protein, both phosphorylation and cleavage of PKC delta were attenuated and DNA fragmentation was markedly suppressed regardless of the presence of angiotensin II. These findings suggest that angiotensin II-induced facilitation of DNA fragmentation under hypoxic conditions is mediated by PKC delta, and the mechanisms can be suppressed by the candesartan mediated blockade of the AT1 receptor.
Original languageEnglish
Pages (from-to)134-140
JournalBrain Research. Molecular Brain Research
Volume135
Issue number1-2
DOIs
Publication statusPublished - 2005

Subject classification (UKÄ)

  • Hematology

Keywords

  • PC12 cell
  • hypoxia
  • DNA fragmentation
  • angiotensin II
  • AT1 receptor
  • protein kinase C delta

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