Restoration of contractile function in isolated cardiomyocytes from failing human hearts by gene transfer of SERCA2a
Restoration of contractile function in isolated cardiomyocytes from failing human hearts by gene transfer of SERCA2a
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DOI：
10.1161/01.cir.100.23.2308
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发表时间：
1999-12-07
期刊：
影响因子：
37.8
通讯作者：
Hajjar, RJ
中科院分区：
文献类型：
--
作者：
del Monte, F;Harding, SE;Hajjar, RJ
背景-衰竭的人类心肌的特征在于异常松弛、肌浆网（SR）Ca 2+摄取不足和负频率响应，这些都与SR Ca 2 + ATP酶（SERCA 2a）泵的不足有关。我们在来自10名终末期心力衰竭患者的人心室肌细胞中过表达SERCA 2a，并检测细胞内Ca 2+处理和收缩功能。SERCA 2a的过表达导致蛋白质表达和泵活性的增加，并诱导更快的收缩速度（每秒缩短26.7 +/- 6.7%对16.6 +/- 2.7%，P < 0.005）和增强的舒张速度（每秒缩短32.0 +/- 10.1%对15.1 +/-2.4%，P < 0.005）。在过度表达SERCA 2a的衰竭心肌细胞中，舒张期Ca 2+降低（270 +/- 26对347 +/- 30 nmol/L，P < 0.005），而收缩期Ca 2+增加（601 +/- 38 vs. 508 +/- 25 nmol/L，P < 0.05），此外，频率响应在过表达SERCA 2a的心肌细胞中正常化。结论-这些结果支持基因-基于人心力衰竭的治疗和靶向特定通路可能为治疗这种疾病提供新的模式。
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.