Targeting phospholamban by gene transfer in human heart failure

Article

关键词: FAILING HUMAN MYOCARDIUM;    SARCOPLASMIC-RETICULUM;    DILATED CARDIOMYOPATHY;    CA2+-ATPASE ACTIVITY;    PROTEIN-LEVELS;    PHOSPHORYLATION;    CONTRACTILITY;    STIMULATION;    SPARE;   

DOI  :  10.1161/hc0802.105564

来源: SCIE

【 摘 要 】

Background-Myocardial cells from failing human hearts are characterized by abnormal calcium handling, a negative force-frequency relationship, and decreased sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) activity. In this study, we tested whether contractile function can be improved by decreasing the inhibitory effects of phospholamban on SERCA2a with adenoviral gene transfer of antisense phospholamban (asPL). Methods and Results-Myocardial cells isolated from 9 patients with end-stage heart failure and 18 donor nonfailing hearts were infected with adenoviruses encoding for either the antisense of phospholamban (Ad.asPL), the SERCA2a gene (Ad.SERCA2a), or the reporter genes beta-galactosidase and green fluorescent protein (Ad.betagal-GFP). Adenoviral gene transfer with Ad.asPL decreased phospholamban expression over 48 hours, increasing the velocity of both contraction and relaxation. Compared with cardiomyocytes infected with Ad.asPL (n=13), human myocytes infected with Ad.betagal-GFP (n=8) had enhanced contraction velocity (20.3+/-3.9% versus 8.7+/-2.6% shortening/second; P<0.01) and relaxation velocity (26.0+/-6.2% versus 8.6+/-4.3% shortening/second; P<0.01). The improvement in contraction and relaxation velocities was comparable to cardiomyocytes infected with Ad.SERCA2a. Failing human cardiomyocytes had decreased contraction and Ca2+ release with increasing frequency (0.1 to 2 Hz). Phospholamban ablation restored the frequency response in the failing cardiomyocytes to normal; increasing frequency resulted in enhanced sarcoplasmic reticulum Ca2+ release and contraction. Conclusion-These results show that gene transfer of asPL can improve the contractile function in failing human myocardium. Targeting phospholamban may provide therapeutic benefits in human heart failure.

【 授权许可】

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