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1Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; 2Laboratory of Cardiovascular Science, National Institutes of Aging, National Institutes of Health, Baltimore, Maryland; 3Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa; 4Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center; 5Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee; and 6Department of Physiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa
Submitted 2 April 2006 ; accepted in final form 17 June 2006
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 whether 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 (WT) littermates were used as controls. AC3-I mice have reduced SR Ca2+ content and are resistant to Iso- and MI-induced apoptosis compared with 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 with AC3-I mice with PLN. These findings indicate CaMKII is proapoptotic in vivo and suggest that regulation of SR Ca2+ content by PLN contributes to the antiapoptotic mechanism of CaMKII inhibition.
myocardial infarction; isoproterenol; programmed cell death; phospholamban
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