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J. Biol. Chem., Vol. 283, Issue 37, 25524-25532, September 12, 2008

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Ca²⁺/Calmodulin-dependent Protein Kinase II-dependent Remodeling of Ca²⁺ Current in Pressure Overload Heart Failure^*

Yanggan Wang¹², Samvit Tandan², Jun Cheng¹, Chunmei Yang, Lan Nguyen, Jessica Sugianto, Janet L. Johnstone, Yuyang Sun^¶, and Joseph A. Hill³

From the Departments of Internal Medicine (Cardiology) and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8573 and the ^¶Department of Pediatrics, Emory University, Atlanta, Georgia 30322

Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) activity is increased in heart failure (HF), a syndrome characterized by markedly increased risk of arrhythmia. Activation of CaMKII increases peak L-type Ca²⁺ current (I_Ca) and slows I_Ca inactivation. Whether these events are linked mechanistically is unknown. I_Ca was recorded in acutely dissociated subepicardial and subendocardial murine left ventricular (LV) myocytes using the whole cell patch clamp method. Pressure overload heart failure was induced by surgical constriction of the thoracic aorta. I_Ca density was significantly larger in subepicardial myocytes than in subendocardial/myocytes. Similar patterns were observed in the cell surface expression of 1c, the channel pore-forming subunit. In failing LV, I_Ca density was increased proportionately in both cell types, and the time course of I_Ca inactivation was slowed. This typical pattern of changes suggested a role of CaMKII. Consistent with this, measurements of CaMKII activity revealed a 2–3-fold increase (p < 0.05) in failing LV. To test for a causal link, we measured frequency-dependent I_Ca facilitation. In HF myocytes, this CaMKII-dependent process could not be induced, suggesting already maximal activation. Internal application of active CaMKII in failing myocytes did not elicit changes in I_Ca. Finally, CaMKII inhibition by internal diffusion of a specific peptide inhibitor reduced I_Ca density and inactivation time course to similar levels in control and HF myocytes. I_Ca density manifests a significant transmural gradient, and this gradient is preserved in heart failure. Activation of CaMKII, a known pro-arrhythmic molecule, is a major contributor to I_Ca remodeling in load-induced heart failure.

Received for publication, April 21, 2008 , and in revised form, July 8, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL-075173 (to J. A. H.), HL-080144 (to J. A. H.), T35-DK066141 (to L. N. and J. S.), and HL-088168 (to Y. W.). This work was also supported by grants from the Donald W. Reynolds Cardiovascular Clinical Research Center (to J. A. H.), American Heart Association Grants 0665178Y (to Y. W.) and 0640084N (to J. A. H.), National Heart Foundation Grant H2007-019 (to Y. W.), The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Dept. of Pediatrics, Emory University, Atlanta, GA 30322.

² Both authors contributed equally to this work.

³ To whom correspondence should be addressed: Division of Cardiology, Dept. of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573. Tel.: 214-648-1400; Fax: 214-648-1450; E-mail: joseph.hill{at}utsouthwestern.edu.

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