AJP - Heart Calcium Transients and Cell-Sarcomere
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Am J Physiol Heart Circ Physiol (July 21, 2006). doi:10.1152/ajpheart.00353.2006
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Submitted on April 2, 2006
Accepted on June 17, 2006

Calmodulin Kinase II Inhibition Protects Against Myocardial Cell Apoptosis in vivo

Yingbo Yang1, Wei-Zhong Zhu2, Mei-ling Joiner3, Rong Zhang1, Carmine V Oddis1, Yue Hou1, Jinying Yang3, Edward E Price1, Linda Gleaves1, Mesut Eren1, Gemin Ni3, Douglas E Vaughan1, Rui-Ping Xiao2, and Mark E. Anderson4*

1 Medicine, Vanderbilt University, Nashville, Tennessee, United States
2 Institute of Aging, NIH, Bethesda, Maryland, United States
3 Medicine, University of Iowa, Iowa City, Iowa, United States
4 Medicine, University of Iowa, Iowa, United States

* To whom correspondence should be addressed. E-mail: mark-e-anderson{at}uiowa.edu.

Inhibition of the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) or depletion of sarcoplasmic reticulum (SR) Ca2+ stores protects against apoptosis from excessive isoproterenol (Iso) stimulation in cultured ventricular myocytes, suggesting that CaMKII inhibition could be a novel approach to reducing cell death in conditions of increased adrenergic tone, such as myocardial infarction (MI), in vivo. We used mice with genetic myocardial CaMKII inhibition due to transgenic expression of a highly specific CaMKII inhibitory peptide (AC3-I) to test if CaMKII was important for apoptosis in vivo. A second line of mice expressed a scrambled, inactive form of AC3-I (AC3-C). AC3-C and wild type littermates (WT) were used as controls. AC3-I mice have reduced SR Ca2+ content and are resistant to Iso and MI-induced apoptosis compared to AC3-C and WT mice. Phospholamban (PLN) is a target for modulation of SR Ca2+ content by CaMKII. PLN-/- mice have increased susceptibility to Iso-induced apoptosis. Verapamil pretreatment prevented Iso-induced apoptosis in PLN-/- mice, indicating the involvement of a Ca2+-dependent pathway. AC3-I and AC3-C mice were bred into a PLN-/- background. Loss of PLN increased and equalized SR Ca2+ content in AC3-I, AC3-C and WT mice and abolished the resistance to apoptosis in AC3-I mice after MI. There was a trend (P=0.07) for increased Iso-induced apoptosis in AC3-I mice lacking PLN compared to AC3-I mice with PLN. These findings indicate CaMKII is pro-apoptotic in vivo and suggest that regulation of SR Ca2+ content by PLN contributes to the anti-apoptotic mechanism of CaMKII inhibition.




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