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  • Title: Rescue of Ca2+ overload-induced left ventricular dysfunction by targeted ablation of phospholamban.
    Author: Tsuji T, Del Monte F, Yoshikawa Y, Abe T, Shimizu J, Nakajima-Takenaka C, Taniguchi S, Hajjar RJ, Takaki M.
    Journal: Am J Physiol Heart Circ Physiol; 2009 Feb; 296(2):H310-7. PubMed ID: 19074672.
    Abstract:
    In failing hearts, a deficiency in sarco(endo)plasmic reticulum Ca2+ -ATPase (SERCA)2a results in abnormal Ca2+ handling and diminished contraction. In addition, a decrease in the phosphorylation of phospholamban (PLB) has been reported. Gene transfer of antisense PLB (asPLB) can improve contractile function in the failing human myocardium. Gene transfer of SERCA2a improves survival and the energy potential in failing hearts. The aim of present study was to evaluate whether enhancement of SERCA2a function prevents acute Ca2+ overload-induced left ventricular (LV) dysfunction in rat hearts. We ablated PLB using adenoviral gene transfer of asPLB by a new and less invasive gene delivery method, which involved a percutaneous technique. Experiments were performed on 13 excised cross-circulated rat hearts: 5 rats underwent sham operations, 4 rats underwent gene transfer of the reporter gene beta-galactosidase (Ad.beta-gal), and 4 rats underwent gene transfer of asPLB (Ad.asPLB). After clearance of high Ca2+ infused into the coronary, there was LV contractile dysfunction associated with the decreased myocardial O2 consumption per beat (Vo2) intercept (equal to decreased Vo2 for Ca2+ handling in excitation-contraction coupling) of the Vo2-systolic pressure-volume area (PVA; total mechanical energy per beat) linear relation in the hearts that underwent sham operation and had been infected with Ad.beta-gal. Hearts that had been infected with Ad.asPLB were rescued from LV contractile dysfunction associated with an unchanged Vo2 intercept of the Vo2-PVA linear relation. We conclude that SERCA2a function enhanced by adenoviral gene transfer of asPLB prevents Ca2+ overload-induced LV contractile dysfunction in terms of mechanical work and especially energetics.
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