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Linkage of β1-adrenergic stimulation to apoptotic heart cell death through protein kinase A–independent activation of Ca2+/calmodulin kinase II
Wei-Zhong Zhu, … , Heping Cheng, Rui-Ping Xiao
Wei-Zhong Zhu, … , Heping Cheng, Rui-Ping Xiao
Published March 1, 2003
Citation Information: J Clin Invest. 2003;111(5):617-625. https://doi.org/10.1172/JCI16326.
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Article

Linkage of β1-adrenergic stimulation to apoptotic heart cell death through protein kinase A–independent activation of Ca2+/calmodulin kinase II

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Abstract

β1-adrenergic receptor (β1AR) stimulation activates the classic cAMP/protein kinase A (PKA) pathway to regulate vital cellular processes from the change of gene expression to the control of metabolism, muscle contraction, and cell apoptosis. Here we show that sustained β1AR stimulation promotes cardiac myocyte apoptosis by activation of Ca2+/calmodulin kinase II (CaMKII), independently of PKA signaling. β1AR-induced apoptosis is resistant to inhibition of PKA by a specific peptide inhibitor, PKI14-22, or an inactive cAMP analogue, Rp-8-CPT-cAMPS. In contrast, the β1AR proapoptotic effect is associated with non–PKA-dependent increases in intracellular Ca2+ and CaMKII activity. Blocking the L-type Ca2+ channel, buffering intracellular Ca2+, or inhibiting CaMKII activity fully protects cardiac myocytes against β1AR-induced apoptosis, and overexpressing a cardiac CaMKII isoform, CaMKII-δC, markedly exaggerates the β1AR apoptotic effect. These findings indicate that CaMKII constitutes a novel PKA-independent linkage of β1AR stimulation to cardiomyocyte apoptosis that has been implicated in the overall process of chronic heart failure.

Authors

Wei-Zhong Zhu, Shi-Qiang Wang, Khalid Chakir, Dongmei Yang, Tong Zhang, Joan Heller Brown, Eric Devic, Brian K. Kobilka, Heping Cheng, Rui-Ping Xiao

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Figure 7

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Overexpression of CaMKII-δC exaggerates β1AR-induced myocyte apoptosis. ...
Overexpression of CaMKII-δC exaggerates β1AR-induced myocyte apoptosis. (a) Confocal imaging of HA immunofluorescence in typical β2AR KO myocytes expressing either β-gal (I), or HA-tagged CaMKII-δC (II, cell surface scan; III, cell nucleus level scan), or HA-tagged CaMKII-δB (IV). (b) Expression of HA-tagged CaMKII-δC assayed by Western blot with an antibody reacting with HA. (c) Dose responses of β1AR-induced increase in apoptotic cells in β2AR KO myocytes infected by Adv–CaMKII-δC (with or without KN93) or Adv–β-gal (n = 6 for each data point).

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