Abstract
Myocardial cells from failing (F) human hearts are characterized by abnormal Ca 2+ handling, a negative force frequency relationship (FFR), and decreased sarcoplasmic reticulum (SR) ATPase activity. We have previously shown that overexpmssion of SERCA2a by adenoviral gene transfer increases SR ATPase activity and enhances Ca 2+ handling both in vitro and in vivo. To test whether contractile function can be restored by overexpression of SERCA2a in human hearts, myocardial cells isolated from 10 patients with end-stage heart failure were infected with adenoviruses encoding either the SERCA2a gene or reporter genes green fluorescent protein (GFP) and /3-galactosidase for 24 hrs. Cells isolated from 2 non-failing hearts were used as controls (C). As shown below, compared to C myocytes, F myocardial cells had prolonged contraction and calcium transient detected by Fura-2. Overexpression of SERCA2a in F myocytes decreased the time course of both contractions and Ca z+ by 19+2% and 27-+4%. F myocytes had decreased Ca 2+ release and an increase in diastolic Ca 2+ with increasing frequency (0.1-1.5Hz). Overexpression of SERCA2a restored the FFR in the F cells to normal: increasing frequency resulted in enhanced SR Ca 2+ release and contraction. These results show that gene transfer of SERCA2a improves the contractile function in F human myocytes. Targeting SERCA2a may provide therapeutic benefits in heart failure.
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