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Multisite phosphorylation of Bcl‐2 via protein kinase C δ facilitates apoptosis of hypertrophic cardiomyocytes
Author(s) -
Sheng JuanJuan,
Chen Yan,
Chang Hui,
Wang YunYing,
Jiao Bo,
Yu ZhiBin
Publication year - 2014
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.12295
Subject(s) - protein kinase c , cytochrome c , apoptosis , mitochondrion , phosphorylation , angiotensin ii , microbiology and biotechnology , tunel assay , chemistry , endocrinology , biology , medicine , biochemistry , blood pressure
Summary Activated protein kinase C δ (PKC δ ) associated with cardiac hypertrophy moves from the cytoplasm to the mitochondria and subsequently triggers the apoptotic signalling pathway. The underlying mechanisms remain unknown. The aim of the present study was to investigate whether mitochondrial translocation of PKC δ phosphorylates multiple sites of Bcl‐2, resulting in an imbalance between Bcl‐2 and Bak or Bax, thus enhancing the susceptibility of hypertrophic cardiomyocytes to angiotensin II (AngII)‐induced apoptosis. Chronic pressure overload was induced by transverse aortic constriction (TAC) in rats. The apoptotic rate increased in hypertrophied cardiomyocytes. In AngII‐treated hearts (10 nmol/L, 60 min), there was an increase in the number of TERMINAL deoxyribonucleotidyl transferase‐mediated dUTP –digoxigenin nick end‐labelling (TUNEL)‐positive cells; PKC δ inhibition with 500 nmol/L δ V1‐1 for 60 min prevented the AngII‐induced increase in apoptosis. In the hypertrophied myocardium, PKC δ expression increased, whereas that of Bcl‐2 decreased compared with the synchronous control. Treatment of hearts with 10 nmol/L AngII for 60 min activated PKC δ and induced translocation of PKC δ to the mitochondria, where activated PKC δ facilitated the phosphorylation of Bcl‐2 at serine‐87 and serine‐70 sites. The multisite phosphorylated Bcl‐2 was released from the mitochondria, and exhibited reduced affinity for Bak and Bax. The imbalance between Bcl‐2 and Bak/Bax induced the release of mitochondrial cytochrome c and then activated the caspase 3 apoptotic pathway during AngII stimulation (10 nmol/L, 60 min) of hypertrophied cardiomyocytes. Inhibition of PKC δ reduced these effects of AngII. The results suggest that PKC δ can counteract the anti‐apoptotic effect of Bcl‐2 and may promote cardiomyocyte apoptosis through multisite phosphorylation of Bcl‐2 in hypertrophied cardiomyocytes.