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Targeted inhibition of sarcoplasmic reticulum CaMKII activity results in alterations of Ca²⁺ homeostasis and cardiac contractility

¹Departments of Genome Science and ²Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio; and ³Department of Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois

Submitted 7 March 2005 ; accepted in final form 29 August 2005

Transgenic (TG) mice expressing a Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) inhibitory peptide targeted to the cardiac myocyte longitudinal sarcoplasmic reticulum (LSR) display reduced phospholamban phosphorylation at Thr¹⁷ and develop dilated myopathy when stressed by gestation and parturition (Ji Y, Li B, Reed TD, Lorenz JN, Kaetzel MA, and Dedman JR. J Biol Chem 278: 25063–25071, 2003). In the present study, these animals (TG) are evaluated for the effect of inhibition of sarcoplasmic reticulum (SR) CaMKII activity on the contractile characteristics and Ca²⁺ cycling of myocytes. Analysis of isolated work-performing hearts demonstrated moderate decreases in the maximal rates of contraction and relaxation (±dP/dt) in TG mice. The response of the TG hearts to increases in load is reduced. The TG hearts respond to isoproterenol (Iso) in a dose-dependent manner; the contractile properties were reduced in parallel to wild-type hearts. Assessment of isolated cardiomyocytes from TG mice revealed 40–47% decrease in the maximal rates of myocyte shortening and relengthening under both basal and Iso-stimulated conditions. Although twitch Ca²⁺ transient amplitudes were not significantly altered, the rate of twitch intracellular Ca²⁺ concentration decline was reduced by 47% in TG myocytes, indicating decreased SR Ca²⁺ uptake function. Caffeine-induced Ca²⁺ transients indicated unaltered SR Ca²⁺ content and Na⁺/Ca²⁺ exchange function. Phosphorylation assays revealed an 30% decrease in the phosphorylation of ryanodine receptor Ser²⁸⁰⁹. Iso stimulation increased the phosphorylation of both phospholamban Ser¹⁶ and the ryanodine receptor Ser²⁸⁰⁹ but not phospholamban Thr¹⁷ in TG mice. This study demonstrates that inhibition of SR CaMKII activity at the LSR results in alterations in cardiac contractility and Ca²⁺ handling in TG hearts.

transgenic mice; calcium/calmodulin-dependent protein kinase II; cardiac contractility; -adrenergic stimulation; phospholamban; ryanodine receptor

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