© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Transgenic rat hearts overexpressing SERCA2a show improved contractility under baseline conditions and pressure overload
aInnere Medizin III, Universitätsklinikum Heidelberg, Heidelberg, Germany
bMedizinische Klinik II, University of Lübeck, Lübeck, Germany
cDepartment of Pathology, University of Lübeck, Germany
dLaboratory for Physiology, VU University Medical Center, Amsterdam, The Netherlands
eMed. Klinik und Poliklinik I—Großhadern, Klinikum der Universität München, Marchioninistr. 15, D-81377 Munich, Germany
* Corresponding author. Tel.: +49-89-7095-3094; fax: +49-89-7095-6094. wfranz{at}helios.med.uni-muenchen.de
Objective: The activity of sarcoplasmic reticulum Ca2+-ATPase (SERCA) is reduced in the failing myocardium. Therefore, transfer of SERCA2a cDNA is considered as a therapeutical approach. The aim of this study was analysis of the long-term effect of SERCA2a overexpression in normal as well as pressure overload challenged myocardium of transgenic rats. Methods: Independent transgenic rat lines were established expressing the rat SERCA2a cDNA specifically in the myocardium resulting in increased SERCA2a protein levels by 30–70%. Simultaneous measurements of isometric contraction and calcium transients were carried out in right ventricular papillary muscle preparations. Hemodynamic parameters were measured in hearts of unchallenged rats as well as 10 weeks after pressure overload induced by abdominal aortic banding. Results: Analysis of calcium handling and contractile parameters in isolated right ventricular papillary muscles revealed significant shortening of intracellular calcium transients and half maximal relaxation times (RT50). Assessing myocardial contractility in working heart preparations, both transgenic rat lines revealed elevated left ventricular pressure, improved systolic and diastolic parameters, attenuated negative force–frequency relation, and a dose-dependent β-adrenergic effect. Aortic banding resulted in reduction of left ventricular pressure and worsening of contraction and relaxation parameters with no differences in mortality in both transgenic (+dP/dt 3084±96 vs. 3938±250 mmHg/s; RT50 47.0±1.2 vs. 36.7±1.4 ms) and wild-type rats (+dP/dt 2695±86 vs. 3297±122 mmHg/s; RT50 53.0±1.6 vs. 44.1±1.4). SERCA2a overexpressing hearts revealed improved hemodynamic parameters compared to wild-type controls. Acceleration of isovolumetric relaxation characterized by the index Tau was directly correlated to SERCA2a protein concentrations. Conclusion: Overexpression of SERCA2a protein results in a positive inotropic effect under baseline conditions remaining preserved under pressure overload without affecting mortality. Therefore therapeutic transfer of SERCA2a may become a potential approach for gene therapy of congestive heart failure. Moreover, transgenic SERCA2a rats will be useful for studies of long-term SERCA2a overexpression in further cardiovascular disease models.
KEYWORDS Ca-pump; Contractile function; Gene therapy; Heart failure; SR (function)
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