© 2000 American Heart Association, Inc.
Cellular Biology |
Impaired Contractile Performance of Cultured Rabbit Ventricular Myocytes After Adenoviral Gene Transfer of Na+-Ca2+ Exchanger
From the Zentrum Innere Medizin (W.S., P.M.L.J., S.E., N.T., O.Z., J.P., G.H.), Abteilung Kardiologie und Pneumologie, Universität Göttingen, Göttingen, Germany; and Departments of Physiology and Medicine (S.A.H., R.S.R., K.D.P.), University of California Los Angeles School of Medicine. Dr Janssen’s present address is Johns Hopkins University, Division of Cardiology, Baltimore, Md.
Correspondence to Gerd Hasenfuss, MD, Georg-August-Universität Göttingen, Zentrum Innere Medizin, Abt. Kardiologie und Pneumologie, Robert-Koch-Str 40, 37075 Göttingen, Germany. E-mail hasenfus{at}med.uni-goettingen.de
Abstract—Na+-Ca2+ exchanger (NCX) gene expression is increased in the failing human heart. We investigated the hypothesis that upregulation of NCX can induce depressed contractile performance. Overexpression of NCX was achieved in isolated rabbit ventricular myocytes through adenoviral gene transfer (Ad-NCX). After 48 hours, immunoblots revealed a virus dose-dependent increase in NCX protein. Adenoviral ß-galactosidase transfection served as a control. The fractional shortening (FS) of electrically stimulated myocytes was analyzed. At 60 min-1, FS was depressed by 15.6% in the Ad-NCX group (n=143) versus the control group (n=163, P<0.05). Analysis of the shortening-frequency relationship showed a steady increase in FS in the control myocytes (n=26) from 0.027±0.002 at 30 min-1 to 0.037±0.002 at 120 min-1 (P<0.05 versus 30 min-1) and to 0.040±0.002 at 180 min-1 (P<0.05 versus 30 min-1). Frequency potentiation of shortening was blunted in NCX-transfected myocytes (n=27). The FS was 0.024±0.002 at 30 min-1, 0.029±0.002 at 120 min-1 (P<0.05 versus 30 min-1, P<0.05 versus control), and 0.026±0.002 at 180 min-1 (NS versus 30 min-1, P<0.05 versus control). Caffeine contractures, which indicate sarcoplasmic reticulum Ca2+ load, were significantly reduced at 120 min-1 in NCX-transfected cells. An analysis of postrest behavior showed a decay of FS with longer rest intervals in control cells. Rest decay was significantly higher in the Ad-NCX group; after 120 seconds of rest, FS was 78±4% in control and 65±3% in the Ad-NCX group (P<0.05) relative to steady-state FS before rest (100%). In conclusion, the overexpression of NCX in rabbit cardiomyocytes results in the depression of contractile function. This supports the hypothesis that upregulation of NCX can result in systolic myocardial failure.
Key Words: calcium • Na+-Ca2+ exchange • heart failure • myocardium • contractility • gene transfer
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