HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 292/3/H1607    most recent 00525.2006v1 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 (13) Citing Articles via Google Scholar Google Scholar Articles by Armoundas, A. A. Articles by William Balke, C. Search for Related Content PubMed PubMed Citation Articles by Armoundas, A. A. Articles by William Balke, C.

Cellular and molecular determinants of altered Ca²⁺ handling in the failing rabbit heart: primary defects in SR Ca²⁺ uptake and release mechanisms

¹Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts; ²Department of Medicine, Division of Molecular Cardiobiology, Johns Hopkins University, and ³Department of Medicine, Division of Cardiology, University of Maryland, Baltimore, Maryland; ⁴Department of Medicine, Division of Cardiology, University of Calgary, Calgary, Alberta, Canada; and ⁵Departments of Medicine and Physiology and Institute of Molecular Medicine, University of Kentucky College of Medicine, Lexington, Kentucky

Submitted 22 May 2006 ; accepted in final form 8 November 2006

Myocytes from the failing myocardium exhibit depressed and prolonged intracellular Ca²⁺ concentration ([Ca²⁺]_i) transients that are, in part, responsible for contractile dysfunction and unstable repolarization. To better understand the molecular basis of the aberrant Ca²⁺ handling in heart failure (HF), we studied the rabbit pacing tachycardia HF model. Induction of HF was associated with action potential (AP) duration prolongation that was especially pronounced at low stimulation frequencies. L-type calcium channel current (I_Ca,L) density (–0.964 ± 0.172 vs. –0.745 ± 0.128 pA/pF at +10 mV) and Na⁺/Ca²⁺ exchanger (NCX) currents (2.1 ± 0.8 vs. 2.3 ± 0.8 pA/pF at +30 mV) were not different in myocytes from control and failing hearts. The amplitude of peak [Ca²⁺]_i was depressed (at +10 mV, 0.72 ± 0.07 and 0.56 ± 0.04 µM in normal and failing hearts, respectively; P < 0.05), with slowed rates of decay and reduced Ca²⁺ spark amplitudes (P < 0.0001) in myocytes isolated from failing vs. control hearts. Inhibition of sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA)2a revealed a greater reliance on NCX to remove cytosolic Ca²⁺ in myocytes isolated from failing vs. control hearts (P < 0.05). mRNA levels of the _1C-subunit, ryanodine receptor (RyR), and NCX were unchanged from controls, while SERCA2a and phospholamban (PLB) were significantly downregulated in failing vs. control hearts (P < 0.05). _1C protein levels were unchanged, RyR, SERCA2a, and PLB were significantly downregulated (P < 0.05), while NCX protein was significantly upregulated (P < 0.05). These results support a prominent role for the sarcoplasmic reticulum (SR) in the pathogenesis of HF, in which abnormal SR Ca²⁺ uptake and release synergistically contribute to the depressed [Ca²⁺]_i and the altered AP profile phenotype.

calcium; ion channels; sarcoplasmic reticulum; pacing tachycardia

This article has been cited by other articles:

				K. Gusev, A. A. Domenighetti, L. M.D. Delbridge, T. Pedrazzini, E. Niggli, and M. Egger Angiotensin II-Mediated Adaptive and Maladaptive Remodeling of Cardiomyocyte Excitation-Contraction Coupling Circ. Res., July 2, 2009; 105(1): 42 - 50. [Abstract] [Full Text] [PDF]

				J. I. Goldhaber and J. H.B. Bridge Loss of Intracellular and Intercellular Synchrony of Calcium Release in Systolic Heart Failure Circ Heart Fail, May 1, 2009; 2(3): 157 - 159. [Full Text] [PDF]

				A. M. Prasad and G. Inesi Effects of thapsigargin and phenylephrine on calcineurin and protein kinase C signaling functions in cardiac myocytes Am J Physiol Cell Physiol, May 1, 2009; 296(5): C992 - C1002. [Abstract] [Full Text] [PDF]

				T. Aiba, G. G. Hesketh, A. S. Barth, T. Liu, S. Daya, K. Chakir, V. L. Dimaano, T. P. Abraham, B. O'Rourke, F. G. Akar, et al. Electrophysiological Consequences of Dyssynchronous Heart Failure and Its Restoration by Resynchronization Therapy Circulation, March 10, 2009; 119(9): 1220 - 1230. [Abstract] [Full Text] [PDF]

				B. Laczy, B. G. Hill, K. Wang, A. J. Paterson, C. R. White, D. Xing, Y.-F. Chen, V. Darley-Usmar, S. Oparil, and J. C. Chatham Protein O-GlcNAcylation: a new signaling paradigm for the cardiovascular system Am J Physiol Heart Circ Physiol, January 1, 2009; 296(1): H13 - H28. [Abstract] [Full Text] [PDF]

				P. T. Caldwell, P. A. Thorne, P. D. Johnson, S. Boitano, R. B. Runyan, and O. Selmin Trichloroethylene Disrupts Cardiac Gene Expression and Calcium Homeostasis in Rat Myocytes Toxicol. Sci., July 1, 2008; 104(1): 135 - 143. [Abstract] [Full Text] [PDF]

				B. S. Stambler and K. R. Laurita Atrial Fibrillation in Heart Failure: Steady Progress but Still a Long Way to Go Circ Arrhythm Electrophysiol, June 1, 2008; 1(2): 77 - 79. [Full Text] [PDF]

				Y.-H. Yeh, R. Wakili, X.-Y. Qi, D. Chartier, P. Boknik, S. Kaab, U. Ravens, P. Coutu, D. Dobrev, and S. Nattel Calcium-Handling Abnormalities Underlying Atrial Arrhythmogenesis and Contractile Dysfunction in Dogs With Congestive Heart Failure Circ Arrhythm Electrophysiol, June 1, 2008; 1(2): 93 - 102. [Abstract] [Full Text] [PDF]