Circulation Research, Vol 75, 443-453, Copyright © 1994 by American Heart Association

ARTICLES

Gene expression of the cardiac Na(+)-Ca2+ exchanger in end-stage human heart failure

R Studer, H Reinecke, J Bilger, T Eschenhagen, M Bohm, G Hasenfuss, H Just, J Holtz and H Drexler
Arbeitsgruppe Molekulare Kardiologie, Universitat Freiburg, Germany.

The regulation of cytosolic Ca2+ concentration during excitation- contraction coupling is altered in the failing human heart. Previous studies have focused on disturbances in Ca2+ release and reuptake from the sarcoplasmic reticulum (SR), whereas functional studies of the cardiac Na(+)-Ca2+ exchanger, another important determinant of myocyte homeostasis, are lacking for the failing human heart. Using a cardiac Na(+)-Ca2+ exchanger cDNA recently cloned from a guinea pig cDNA library, we investigated the gene expression of the cardiac Na(+)-Ca2+ exchanger in relation to the SR Ca(2+)-ATPase. Expression of both genes was quantified in left ventricular myocardium from 24 failing human cardiac explants and 7 control heart samples in relation to beta-myosin heavy chain mRNA by slot blot analysis. Compared with patients with nonfailing hearts, patients with dilated cardiomyopathy (DCM, n = 13) showed a 55% increase in Na(+)-Ca2+ exchanger mRNA levels (P < .05 versus control value) and a 41% increase in patients with coronary artery disease (CAD, n = 11). In the same hearts, SR Ca(2+)-ATPase mRNA levels were decreased by 50% in DCM and by 45% in CAD (P < .05 for both versus control value). There was a positive correlation between Na(+)- Ca2+ exchanger and SR Ca(2+)-ATPase mRNA levels both in normal and failing human hearts, albeit with different slopes and intercepts of the regression line. The Na(+)-Ca2+ exchanger protein levels as assessed by Western blot analysis and normalized to beta-myosin heavy chain protein were increased in DCM and CAD (P < .05 and P < .01 versus control value, respectively), whereas SR Ca(2+)-ATPase protein levels were reduced (P < .05 for both groups versus control values). Thus, the Na(+)-Ca2+ exchanger gene expression is enhanced in failing human hearts and may, in part, compensate for the depressed SR function with regard to diastolic Ca2+ removal.

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				P. M. Heerdt, J. W. Holmes, B. Cai, A. Barbone, J. D. Madigan, S. Reiken, D. L. Lee, M. C. Oz, A. R. Marks, and D. Burkhoff Chronic Unloading by Left Ventricular Assist Device Reverses Contractile Dysfunction and Alters Gene Expression in End-Stage Heart Failure Circulation, November 28, 2000; 102(22): 2713 - 2719. [Abstract] [Full Text] [PDF]

				J. L. Greenstein, R. Wu, S. Po, G. F. Tomaselli, and R. L. Winslow Role of the Calcium-Independent Transient Outward Current Ito1 in Shaping Action Potential Morphology and Duration Circ. Res., November 24, 2000; 87(11): 1026 - 1033. [Abstract] [Full Text] [PDF]

				N. Satoh, T. M. Suter, R. Liao, and W. S. Colucci Chronic {alpha}-Adrenergic Receptor Stimulation Modulates the Contractile Phenotype of Cardiac Myocytes In Vitro Circulation, October 31, 2000; 102(18): 2249 - 2254. [Abstract] [Full Text] [PDF]

				K. Schlotthauer and D. M. Bers Sarcoplasmic Reticulum Ca2+ Release Causes Myocyte Depolarization : Underlying Mechanism and Threshold for Triggered Action Potentials Circ. Res., October 27, 2000; 87(9): 774 - 780. [Abstract] [Full Text] [PDF]

				S. M. Pogwizd Increased Na+-Ca2+ Exchanger in the Failing Heart Circ. Res., October 13, 2000; 87(8): 641 - 643. [Full Text] [PDF]

				I. A. Hobai and B. O'Rourke Enhanced Ca2+-Activated Na+-Ca2+ Exchange Activity in Canine Pacing-Induced Heart Failure Circ. Res., October 13, 2000; 87(8): 690 - 698. [Abstract] [Full Text] [PDF]

				P. Trouve, F. Carre, I. Belikova, C. Leclercq, T. Dakhli, L. Soufir, I. Coquard, J. Ramirez-Gil, and D. Charlemagne Na+-K+-ATPase alpha 2-isoform expression in guinea pig hearts during transition from compensation to decompensation Am J Physiol Heart Circ Physiol, October 1, 2000; 279(4): H1972 - H1981. [Abstract] [Full Text] [PDF]

				W. Schillinger, P. M. L. Janssen, S. Emami, S. A. Henderson, R. S. Ross, N. Teucher, O. Zeitz, K. D. Philipson, J. Prestle, and G. Hasenfuss Impaired Contractile Performance of Cultured Rabbit Ventricular Myocytes After Adenoviral Gene Transfer of Na+-Ca2+ Exchanger Circ. Res., September 29, 2000; 87(7): 581 - 587. [Abstract] [Full Text] [PDF]

				D. M. Bers Calcium Fluxes Involved in Control of Cardiac Myocyte Contraction Circ. Res., August 18, 2000; 87(4): 275 - 281. [Full Text] [PDF]

				H. Yokoyama, S. Gunasegaram, S. E. Harding, and M. Avkiran Sarcolemmal Na+/H+ exchanger activity and expression in human ventricular myocardium J. Am. Coll. Cardiol., August 1, 2000; 36(2): 534 - 540. [Abstract] [Full Text] [PDF]

				B. Linck, P. Bokník, S. Huke, U. Kirchhefer, J. Knapp, H. Lüss, F. U. Müller, J. Neumann, Z. Tanriseven, U. Vahlensieck, et al. Functional Properties of Transgenic Mouse Hearts Overexpressing Both Calsequestrin and the Na+-Ca2+ Exchanger J. Pharmacol. Exp. Ther., August 1, 2000; 294(2): 648 - 657. [Abstract] [Full Text]

				J. A. Wasserstrom, E. Holt, I. Sjaastad, P. K. Lunde, A. Odegaard, and O. M. Sejersted Altered E-C coupling in rat ventricular myocytes from failing hearts 6 wk after MI Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H798 - H807. [Abstract] [Full Text] [PDF]

				C. Piper, J. Bilger, E.-M. Henrichs, H.-P. Schultheiss, D. Horstkotte, and A. Doerner Is myocardial Na+/Ca2+ exchanger transcription a marker for different stages of myocardial dysfunction? Quantitative polymerase chain reaction of the messenger RNA in endomyocardial biopsies of patients with heart failure J. Am. Coll. Cardiol., July 1, 2000; 36(1): 233 - 241. [Abstract] [Full Text] [PDF]

				B. C Knollmann, B. E C Knollmann-Ritschel, N. J Weissman, L. R Jones, and M. Morad Remodelling of ionic currents in hypertrophied and failing hearts of transgenic mice overexpressing calsequestrin J. Physiol., June 1, 2000; 525(2): 483 - 498. [Abstract] [Full Text] [PDF]

				W. W. Brooks, O. H. L. Bing, M. O. Boluyt, A. Malhotra, J. P. Morgan, N. Satoh, W. S. Colucci, and C. H. Conrad Altered Inotropic Responsiveness and Gene Expression of Hypertrophied Myocardium With Captopril Hypertension, June 1, 2000; 35(6): 1203 - 1209. [Abstract] [Full Text] [PDF]

				G. U. Ahmmed, P. H. Dong, G. Song, N. A. Ball, Y. Xu, R. A. Walsh, and N. Chiamvimonvat Changes in Ca2+ Cycling Proteins Underlie Cardiac Action Potential Prolongation in a Pressure-Overloaded Guinea Pig Model With Cardiac Hypertrophy and Failure Circ. Res., March 17, 2000; 86(5): 558 - 570. [Abstract] [Full Text] [PDF]

				Y. Qu, A. Ghatpande, N. El-Sherif, and M. Boutjdir Gene expression of Na+/Ca2+ exchanger during development in human heart Cardiovasc Res, March 1, 2000; 45(4): 866 - 873. [Abstract] [Full Text] [PDF]

				L. S Maier, C. Schwan, W. Schillinger, K. Minami, U. Schutt, and B. Pieske Gingerol, isoproterenol and ouabain normalize impaired post-rest behavior but not force-frequency relation in failing human myocardium Cardiovasc Res, March 1, 2000; 45(4): 913 - 924. [Abstract] [Full Text] [PDF]

				R. G Matteo and C. S. Moravec Immunolocalization of annexins IV, V and VI in the failing and non-failing human heart Cardiovasc Res, March 1, 2000; 45(4): 961 - 970. [Abstract] [Full Text] [PDF]

				C. A. Walker, F. A. Crawford Jr, and F. G. Spinale MYOCYTE CONTRACTILE DYSFUNCTION WITH HYPERTROPHY AND FAILURE: RELEVANCE TO CARDIAC SURGERY J. Thorac. Cardiovasc. Surg., February 1, 2000; 119(2): 388 - 400. [Full Text] [PDF]

				U Ravens and D Dobrev Regulation of sarcoplasmic reticulum Ca2+-ATPase and phospholamban in the failing and nonfailing heart Cardiovasc Res, January 1, 2000; 45(1): 245 - 252. [Full Text] [PDF]

				S. M. Pogwizd, M. Qi, W. Yuan, A. M. Samarel, and D. M. Bers Upregulation of Na+/Ca2+ Exchanger Expression and Function in an Arrhythmogenic Rabbit Model of Heart Failure Circ. Res., November 26, 1999; 85(11): 1009 - 1019. [Abstract] [Full Text] [PDF]

				B. Bartling, H. Milting, H. Schumann, D. Darmer, L. Arusoglu, M. M. Koerner, A. El-Banayosy, R. Koerfer, J. Holtz, and H.-R. Zerkowski Myocardial Gene Expression of Regulators of Myocyte Apoptosis and Myocyte Calcium Homeostasis During Hemodynamic Unloading by Ventricular Assist Devices in Patients With End-Stage Heart Failure Circulation, November 9, 1999; 100 (2009): II-216 - II-223. [Abstract] [Full Text] [PDF]