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Calmodulin kinase II inhibition protects against myocardial cell apoptosis in vivo

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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