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(Circulation Research. 2003;93:132.)
© 2003 American Heart Association, Inc.

Cellular Biology

Effects of Adenovirus-Mediated Sorcin Overexpression on Excitation-Contraction Coupling in Isolated Rabbit Cardiomyocytes

Tim Seidler, Stewart L.W. Miller, Christopher M. Loughrey, Astrid Kania, Annika Burow, Sarah Kettlewell, Nils Teucher, Stefan Wagner, Harald Kögler, Marian B. Meyers, Gerd Hasenfuss, Godfrey L. Smith

From the Department of Cardiology and Pneumology (T.S., A.K., A.B., N.T., S.W., H.K., G.H.), Georg-August-University Goettingen, Goettingen, Germany; Institute of Biomedical and Life Sciences (S.L.W.M., S.K., G.L.S.), University of Glasgow, Glasgow, UK; Institute of Comparative Medicine (C.M.L.), University of Glasgow Veterinary School, University of Glasgow, Glasgow, UK; and Department of Medicine (M.B.M.), Cardiology Division, New York University School of Medicine, New York, NY.

Correspondence to G. Hasenfuss, MD, Georg-August-Universität Goettingen, Abt. Kardiologie & Pneumologie, Robert-Koch-Strasse 40, 37075 Goettingen, Germany. E-mail hasenfus{at}med.uni-goettingen.de

To evaluate the effect of sorcin on cardiac excitation-contraction coupling, adult rabbit ventricular myocytes were transfected with a recombinant adenovirus coding for human sorcin (Ad-sorcin). A ß-galactosidase adenovirus (Ad-LacZ) was used as a control. Fractional shortening in response to 1-Hz field stimulation (at 37°C) was significantly reduced in Ad-sorcin–transfected myocytes compared with control myocytes (2.10±0.05% [n=311] versus 2.42±0.06% [n=312], respectively; P<0.001). Action potential duration (at 20°C) was significantly less in the Ad-sorcin group (458±22 ms, n=11) compared with the control group (520±19 ms, n=10; P<0.05). In voltage-clamped, fura 2–loaded myocytes (20°C), a reduced peak-systolic and end-diastolic [Ca²⁺]_i was observed after Ad-sorcin transfection. L-type Ca²⁺ current amplitude and time course were unaffected. Caffeine-induced Ca²⁺ release from the sarcoplasmic reticulum (SR) and the accompanying inward Na⁺-Ca²⁺ exchanger (NCX) current revealed a significantly lower SR Ca²⁺ content and faster Ca²⁺-extrusion kinetics in Ad-sorcin–transfected cells. Higher NCX activity after Ad-sorcin transfection was confirmed by measuring the NCX current-voltage relationship. ß-Escin–permeabilized rabbit cardiomyocytes were used to study the effects of sorcin overexpression on Ca²⁺ sparks imaged with fluo 3 at 145 to 160 nmol/L [Ca²⁺] using a confocal microscope. Under these conditions, caffeine-mediated SR Ca²⁺ release was not different between the two groups. Spontaneous spark frequency, duration, width, and amplitude were lower in sorcin-overexpressing myocytes. In summary, sorcin overexpression in rabbit cardiomyocytes decreased Ca²⁺-transient amplitude predominately by lowering SR Ca²⁺ content via increased NCX activity. The effect of sorcin overexpression on Ca²⁺ sparks indicates an effect on the ryanodine receptor that may also influence excitation-contraction coupling.

Key Words: excitation-contraction coupling • calcium • cardiac myocytes • adenoviral gene transfer

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