Increased SR Ca2+ cycling contributes to improved contractile performance in SERCA2a-overexpressing transgenic rats

doi:10.1016/j.cardiores.2005.05.006

Cardiovascular Research 2005 67(4):636-646; doi:10.1016/j.cardiores.2005.05.006

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Increased SR Ca²⁺ cycling contributes to improved contractile performance in SERCA2a-overexpressing transgenic rats

Lars S. Maier^a, Christian Wahl-Schott^b^,d, Wiebke Horn^a, Stefan Weichert^a, Christian Pagel^a, Stefan Wagner^a, Nataliya Dybkova^a, Oliver J. Müller^c, Michael Näbauer^d, Wolfgang-M. Franz^d^,*^,1 and Burkert Pieske^a^,1

^aAbt. Kardiologie and Pneumologie/Herzzentrum, Georg-August-Universität Göttingen, Germany
^bPharmakologie für Naturwissenschaften, Dept. Pharmazie, LMU München, Germany
^cInnere Medizin III, Universitätsklinikum Heidelberg, Germany
^dMed. Klinik and Poliklinik I-Großhadern, Marchioninistr. 15, 81377 München, Germany

^* Corresponding author. Email address: wolfgang.franz{at}med.uni-muenchen.de

Objective: Heart failure is associated with reduced functionof sarcoplasmic reticulum (SR) Ca²⁺-ATPase (SERCA2a) but increasedfunction of sarcolemmal Na⁺/Ca²⁺ exchanger (NCX), leading todecreased SR Ca²⁺ content and loss of frequency-potentiationof contractile force. We reported that SERCA2a-overexpressionin transgenic rat hearts (TG) results in improved contractility.However, it was not clear whether TG have improved contractilitydue to frequency-dependent improved SR Ca²⁺ handling.

Methods: Therefore, we characterized TG (n = 35) vs. wild-type(WT) control rats (n = 39) under physiological conditions (37°C, stimulation rate <8 Hz). Twitch force, intracellularCa²⁺ transients ([Ca²⁺]_i), and SR Ca²⁺ content were measuredin isolated muscles. The contribution of transsarcolemmal Ca²⁺influx (I_Ca) through L-type Ca²⁺ channels (LTCC) and reversemode NCX (I_Na/Ca) to Ca²⁺ cycling were studied in isolated myocytes.

Results: With increasing frequency, force increased in TG musclesby 168 ± 35% (8 Hz; P<0.05) and SR Ca²⁺ content increasedby maximally 118 ± 31% (4 Hz; P<0.05). In WT, therewas a flat force-frequency response without changes in SR Ca²⁺content. Relaxation parameters of force and [Ca²⁺]_i decay wereaccelerated at each frequency in TG vs. WT by $~$ 10%. At prolongedrest intervals (<240 s), force and SR Ca²⁺ content increasedsignificantly more in TG. Consequently, absolute SR Ca²⁺ contentmeasured in myocytes was increased $~$ 2-fold in TG. TranssarcolemmalCa²⁺ fluxes estimated by I_Ca (at 0 mV –10.2 ± 1.1vs. –16.9 ± 1.3 pA/pF) and I_Na/Ca (0.17 ±0.02 vs. 0.46 ± 0.05 pA/pF) were decreased in TG vs.WT (P<0.05), whereas NCX and LTCC protein expression wasonly slightly reduced (P = n.s.).

Conclusion: In summary, SERCA2a-overexpression improved contractilityin a frequency-dependent way due to increased SR Ca²⁺ loadingwhereas transsarcolemmal Ca²⁺ fluxes were decreased.

KEYWORDS Calcium (cellular); Contractile function; E–C coupling; Transgenic animal models; SR (function)

¹ Equal contribution.

Time for primary review 24 days

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