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This Article Full Text Full Text (PDF) All Versions of this Article: 290/2/H599    most recent 00214.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Ji, Y. Articles by Dedman, J. R. Search for Related Content PubMed PubMed Citation Articles by Ji, Y. Articles by Dedman, J. R.

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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