Rescue of Ca 2+ overload-induced left ventriclur dysfunction by targeted ablation of phospholamban

Tsuyoshi Tsuji, Federica Del Monte, Yoshiro Yoshikawa, Takehisa Abe, Juichiro Shimizu, Chikako Nakajima-Takenaka, Shigeki Taniguchi, Roger J. Hajjar, Miyako Takaki

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35 Scopus citations


In failing hearts, a deficiency in sarco(endo)plasmic reticulum Ca 2+-ATPase (SERCA)2a results in abnormal Ca 2+ 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 Ca 2+ overload-induced left ventricular (LV) dysfunction in rat hearts. We ablated PLB using adeno- viral 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 (3-galactosidase (Ad.(3-gal), and 4 rats underwent gene transfer of asPLB (Ad.asPLB). After clearance of high Ca 2+ infused into the coronary, there was LV contractile dysfunction associated with the decreased myocardial O 2 consumption per beat (VO 2) intercept (equal to decreased Vo 2 for Ca 2+ handling in excitation-contraction coupling) of the VO 2-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.(3-gal. Hearts that had been infected with Ad.asPLB were rescued from LV contractile dysfunction associated with an unchanged VO 2 intercept of the VO 2-PVA linear relation. We conclude that SERCA2a function enhanced by adenoviral gene transfer of asPLB prevents Ca 2+ overload-induced LV contractile dysfunction in terms of mechanical work and especially energetics.

Original languageEnglish
Pages (from-to)H310-H317
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Issue number2
StatePublished - Feb 2009
Externally publishedYes


  • Cardiac function
  • In vivo gene transfer
  • Myocardial o consumption per beat
  • Percutaneous
  • Systolic pres sure-volume area


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