UTSUGISAWA Taiju
   Department   School of Medicine(Tokyo Women's Medical University Hospital), School of Medicine
   Position   Assistant Professor
Article types Original article
Language English
Peer review Peer reviewed
Title Candesartan prevents angiotensin II-induced facilitation of hypoxic neuronal damage through PKCdelta inhibition.
Journal Formal name:Brain research. Molecular brain research
Abbreviation:Brain Res Mol Brain Res
ISSN code:0169328X/0169328X
Domestic / ForeginForegin
Volume, Issue, Page 135(1-2),pp.134-140
Author and coauthor Utsugisawa Kimiaki, Nagane Yuriko, Utsugisawa Taiju, Obara Daiji, Terayama Yasuo
Publication date 2005/04
Summary To investigate the role of protein kinase Cdelta (PKCdelta) 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 PKCdelta phosphorylated at Ser(643) before hypoxia, promoted the cleavage of PKCdelta to its catalytic fragment, and fostered the progression of DNA fragmentation after hypoxia. Candesartan inhibited both phosphorylation and cleavage of PKCdelta and suppressed the angiotensin II-induced facilitation of DNA fragmentation under hypoxic/reoxygenation conditions. However, PD123319, an AT2 receptor antagonist, influenced neither PKCdelta nor the angiotensin II-induced facilitation of DNA fragmentation. Furthermore, in PC12 cells expressing the ATP-binding mutant of PKCdelta (PKCdelta(K376R)) acting as a dominant-negative protein, both phosphorylation and cleavage of PKCdelta 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 PKCdelta, and the mechanisms can be suppressed by the candesartan mediated blockade of the AT1 receptor.
DOI 10.1016/j.molbrainres.2004.12.004
PMID 15857676