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This Article Full Text Full Text (PDF) All Versions of this Article: 296/2/H310    most recent 00975.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Tsuji, T. Articles by Takaki, M. Search for Related Content PubMed PubMed Citation Articles by Tsuji, T. Articles by Takaki, M.

Rescue of Ca²⁺ overload-induced left ventriclur dysfunction by targeted ablation of phospholamban

¹Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; and Departments of ²Thoracic and Cardiovascular Surgery and ³Physiology II, Nara Medical University, Nara, Japan

Submitted 8 September 2008 ; accepted in final form 1 December 2008

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 β-galactosidase (Ad.β-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.β-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.

in vivo gene transfer; percutaneous; cardiac function; systolic pressure-volume area; myocardial O₂ consumption per beat

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