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

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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Role of CaMKII and calcineurin in the β1AR-mediated apoptotic effect. Af...
Role of CaMKII and calcineurin in the β1AR-mediated apoptotic effect. After β1β2 DKO myocytes were infected by Adv-β1AR, cells were pretreated with the CaMKII inhibitors AIP (10 μM) or KN93 (0.5 μM) or the inactive KN93 analogue KN92 (2 μM); with the calcineurin inhibitors FK506 (10 μM) or cyclosporin A (5 μM); with the PKA inhibitor PKI (5 μM); or with the Ca2+ channel blocker nifedipine (1 μM), all for 1 hour (except 3 hours for AIP) prior to administration of 1 μM ISO. Apoptosis was assessed after incubation for another 24 hours. (a) AIP or KN93 fully protected cardiomyocytes against ISO-elicited apoptosis. Arrows indicate TUNEL-positive nuclei. (b) The ISO-induced increase in TUNEL-positive cells was prevented by AIP or KN93, but not the inactive KN93 analogue KN92 or the calcineurin inhibitors FK506 or cyclosporin A. n = 4–8. *P < 0.01 versus ISO-untreated groups or those treated with KN93 or AIP. (c) ISO-induced DNA laddering in the absence (control) or presence of KN93, PKI, or the βAR antagonist propranolol. Similar results were obtained in four other experiments. CyA, cyclosporin A.