Modulation of ventricular function through gene transfer in vivo
Modulation of ventricular function through gene transfer in vivo
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DOI：
10.1073/pnas.95.9.5251
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发表时间：
1998-04-28
影响因子：
11.1
通讯作者：
Rosenzweig, A
中科院分区：
文献类型：
--
作者：
Hajjar, RJ;Schmidt, U;Rosenzweig, A
我们使用了一种基于导管的技术，以实现广义的心脏基因转移在体内，并改变心脏功能的过表达受磷蛋白（PL），调节活性的肌浆网钙ATP酶（SERCA 2a）。通过使用这种方法，用5 × 10（9）pfu的携带PL、β-半乳糖苷酶（β-gal）或修饰的绿色荧光蛋白（EGFP）的cDNA的重组腺病毒载体在体内转导大鼠心脏。Western blot分析表明，PL基因转染的大鼠心室PL比Ad β gal基因转染的大鼠心室PL增加2.8倍，感染后第2天，PL基因转染的大鼠心室峰值左室压降低（58.3 +/- 12.9 mmHg，n = 8）与未感染心脏相比（92.5 +/- 3.5 mmHg，n = 6）或感染Ad.beta gal的心脏（92.6 +/- 5.9 mmHg，n = 6），压力上升和压力下降的峰值速率与未感染的心脏相比，在PL过表达的心脏中，心肌细胞的舒张压（+3，210 +/- 298 mmHg/s，-2，117 +/- 178 mmHg/s，n = 8）降低（+5，225 +/- 136 mmHg/s，-3，805 +/- 97 mmHg/s，n = 6）或感染Ad.beta gal的心脏（+5，108 +/- 167 mmHg/s，-3，765 +/- 121 mmHg/s，n = 6），PL高表达组左室舒张时间常数明显增加与未感染的心脏（18.5 +/- 1.0 ms，n = 6）或用Ad.beta gal感染的心脏（20.8 +/- 2.1 ms，n = 6）相比，感染的心脏（33.4 +/- 3.2 ms，n = 8）。这些心室功能的差异在感染后7天保持不变。这些研究为利用体细胞基因转移调节体内整体心脏功能的实验或治疗应用开辟了前景。
We used a catheter-based technique to achieve generalized cardiac gene transfer in vivo and to alter cardiac function by overexpressing phospholamban (PL) which regulates the activity of the sarcoplasmic reticulum Ca2+ ATPase (SERCA2a). By using this approach, rat hearts were transduced in vivo with 5 x 10(9) pfu of recombinant adenoviral vectors carrying cDNA for either PL, beta-galactosidase (beta-gal), or modified green fluorescent protein (EGFP). Western blot analysis of ventricles obtained from rats transduced by Ad.PL showed a 2.8-fold increase in PL compared with hearts transduced by Ad.beta gal, Two days after infection, rat hearts transduced with Ad.PL had lower peak left ventricular pressure (58.3 +/- 12.9 mmHg, n = 8) compared with uninfected hearts (92.5 +/- 3.5 mmHg, n = 6) or hearts infected with Ad.beta gal (92.6 +/- 5.9 mmHg, n = 6), Both peak rate of pressure rise and pressure fall (+3, 210 +/- 298 mmHg/s, -2, 117 +/- 178 mmHg/s, n = 8) were decreased in hearts overexpressing PL compared with uninfected hearts (+5, 225 +/- 136 mmHg/s, -3, 805 +/- 97 mmHg/s, n = 6) or hearts infected with Ad.beta gal (+5, 108 +/- 167 mmHg/s, -3, 765 +/- 121 mmHg/s, n = 6), The time constant of left ventricular relaxation increased significantly in hearts overexpressing PL (33.4 +/- 3.2 ms, n = 8) compared with uninfected hearts (18.5 +/- 1.0 ms, n = 6) or hearts infected with Ad.beta gal (20.8 +/- 2.1 ms, n = 6). These differences in ventricular function were maintained 7 days after infection. These studies open the prospect of using somatic gene transfer to modulate overall cardiac function in vivo for either experimental or therapeutic applications.