Adenoviral gene transfer of SERCA2a improves left-ventricular function in aortic-banded rats in transition to heart failure
Adenoviral gene transfer of SERCA2a improves left-ventricular function in aortic-banded rats in transition to heart failure
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DOI：
10.1073/pnas.97.2.793
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发表时间：
2000-01-18
影响因子：
11.1
通讯作者：
Hajjar, RJ
中科院分区：
文献类型：
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作者：
Miyamoto, MI;del Monte, F;Hajjar, RJ
在人类和实验性心力衰竭模型中，肌浆网钙ATPase(SERCA2a)活性降低，导致钙离子异常处理。钙代谢紊乱已被证明是心力衰竭所致收缩功能障碍的重要原因。我们研究了增加SERCA2a表达是否可以改善通过造成大鼠升主动脉缩窄而获得的心力衰竭动物模型的心功能。在从代偿性肥厚到心力衰竭的转变过程中，经过19-23周的条带(由>；缩短率下降25%记录)，大鼠被随机接受携带SERCA2a基因的腺病毒(Ad.SERCA2a，n=13)或β-半乳糖苷酶(Ad.beta Gal，n=14)，通过基于导管的技术。与非衰竭假手术大鼠(n=11)相比，感染Ad.beta Gal的衰竭大鼠的SERCA2a表达和SERCA2a活性显著降低。此外，这些衰竭心脏还降低了左心室收缩压、左心室内压最大上升和下降速率(+dp/dt、-dp/dt)和等容舒张率(Tau)。SERCA2a过表达使SERCA2a表达和ATPase活性恢复到正常水平。此外，感染Ad.SERCA2a的大鼠左室收缩压、+dp/dt、-dp/dt和等容舒张率(Tau)显著改善，恢复到与假手术大鼠相当的水平。在这项研究中，我们发现，在心力衰竭动物模型中，SERCA2a蛋白水平和活性降低，存在严重的收缩功能障碍，体内过表达SERCA2a可以使收缩和舒张期功能恢复到正常水平。
In human and experimental models of heart failure, sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) activity is decreased, resulting in abnormal calcium handling. The disturbances in calcium metabolism have been shown to contribute significantly to the contractile dysfunction observed in heart failure. We investigated whether increasing SERCA2a expression can improve ventricular function in an animal model of heart failure obtained by creating ascending aortic constriction in rats. After 19-23 wk of banding during the transition from compensated hypertrophy to heart failure (documented by >25% decrease in fractional shortening), rats were randomized to receive either an adenovirus carrying the SERCA2a gene (Ad.SERCA2a, n = 13) or beta-galactosidase (Ad.beta gal, n = 14) by using a catheter-based technique. The failing hearts infected with Ad.beta gal were characterized by a significant decrease in SERCA2a expression and a decrease in SERCA2a activity compared with nonfailing sham-operated rats (n = 11). In addition, these failing hearts had reduced left-ventricular systolic: pressure, maximal rate of left-ventricular pressure rise and decline (+dP/dt, -dP/dt), and rate of isovolumic: relaxation (tau). Overexpression of SERCA2a restored both SERCA2a expression and ATPase activity to nonfailing levels. Furthermore, rats infected with Ad.SERCA2a had significant improvement in left-ventricular systolic pressure, +dP/dt, -dP/dt, and rate of isovolumic relaxation (tau) normalizing them back to levels comparable to sham-operated rats. In this study, we show that in an animal model of heart failure where SERCA2a protein levels and activity are decreased and severe contractile dysfunction is present, overexpression of SERCA2a in vivo restores both systolic and diastolic function to normal levels.