Restoration of contractile function in isolated cardiomyocytes from failing human hearts by gene transfer of SERCA2a

Article

关键词: SARCOPLASMIC-RETICULUM CA2+-ATPASE;    ISOLATED VENTRICULAR MYOCYTES;    DILATED CARDIOMYOPATHY;    FAILURE;    EXPRESSION;    MYOCARDIUM;    PHOSPHOLAMBAN;    ATPASE;   

DOI  :  10.1161/01.CIR.100.23.2308

来源: SCIE

【 摘 要 】

Background-Failing human myocardium is characterized by abnormal relaxation, a deficient sarcoplasmic reticulum (SR) Ca2+ uptake, and a negative frequency response, which have all been related to a deficiency in the SR Ca2+ ATPase (SERCA2a) pump. Methods and Results-To test the hypothesis that an increase in SERCA2a could improve contractile function in cardiomyocytes, we overexpressed SERCA2a in human ventricular myocytes from 10 patients with end-stage heart failure and examined intracellular Ca2+ handling and contractile function. Overexpression of SERCA2a resulted in an increase in both protein expression and pump activity and induced a faster contraction velocity (26.7 +/- 6.7% versus 16.6 +/- 2.7% shortening per second, P < 0.005) and enhanced relaxation velocity (32.0 +/- 10.1% versus 15.1 +/- 2.4%, P < 0.005). Diastolic Ca2+ was decreased in failing cardiomyocytes overexpressing SERCA2a (270 +/- 26 versus 347 +/- 30 nmol/L, P < 0.005), whereas systolic Ca2+ was increased (601 +/- 38 versus 508 +/- 25 nmol/L, P < 0.05), In addition, the frequency response was normalized in cardiomyocytes overexpressing SERCA2a. Conclusions-These results support the premise that gene-based therapies and targeting of specific pathways in human heart failure may offer a new modality for the treatment of this disease.

【 授权许可】

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