Enhancement of cardiac function after adenoviral-mediated in vivo intracoronary β2-adrenergic receptor gene delivery
Enhancement of cardiac function after adenoviral-mediated in vivo intracoronary β2-adrenergic receptor gene delivery
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DOI：
10.1172/jci6026
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发表时间：
1999-07-01
影响因子：
15.9
通讯作者：
Koch, WJ
中科院分区：
文献类型：
--
作者：
Maurice, JP;Hata, JA;Koch, WJ
外源性基因转染改变心脏功能是治疗心力衰竭（HF）等心血管疾病的一种潜在的新的治疗策略。在实现改变心脏功能的基因治疗方法之前，必须建立有效和可重复的体内基因技术，以有效地将转基因转移到心肌。我们一直在验证这样一个假设，即对心力衰竭患者受损的心肌β-肾上腺素能受体（β-AR）系统进行遗传操作可以增强心脏功能。我们已经使用冠状动脉内方法将腺病毒转基因，包括人β（2）-AR（Adeno-beta（2）AR），递送到兔子的心肌中。导管介导的Adeno-beta（2）AR递送产生弥漫性多腔心肌表达，在基因转移后1周达到峰值。总共5 × 10（11）个腺病毒-β（2）AR病毒颗粒可重复地在心脏中产生5至10倍的β-AR过表达，与接受空腺病毒的对照兔相比，在递送后7天和21天，其导致体内血流动力学功能增加。几个生理参数，包括dP/dt（最大值）作为收缩力的测量，显着增强的基础，并表现出增加的β-激动剂异丙肾上腺素的反应。我们的研究结果表明，全球心肌在体内基因传递是可能的，β-AR密度的遗传操纵可以导致增强心脏性能。因此，HF中丢失受体的替代可能代表新的正性肌力治疗。
Exogenous gene delivery to alter the function of the heart is a potential novel therapeutic strategy for treatment of cardiovascular diseases such as heart failure (HF). Before gene therapy approaches to alter cardiac function can be realized, efficient and reproducible in vivo gene techniques must be established to efficiently transfer transgenes globally to the myocardium. We have been testing the hypothesis that genetic manipulation of the myocardial beta-adrenergic receptor (beta-AR) system, which is impaired in HF, can enhance cardiac function. We have delivered adenoviral transgenes, including the human beta(2)-AR (Adeno-beta(2)AR), to the :myocardium of rabbits using an intracoronary approach. Catheter-mediated Adeno-beta(2)AR delivery produced diffuse multichamber myocardial expression, peaking 1 week after gene transfer. A total of 5 x 10(11) viral particles of Adeno-beta(2)AR reproducibly produced 5- to 10-fold beta-AR overexpression in the heart, which, at 7 and 21 days after delivery, resulted in increased in vivo hemodynamic function compared with control rabbits that received an empty adenovirus. Several physiological parameters, including dP/dt(max) as a measure of contractility, were significantly enhanced basally and showed increased responsiveness to the beta-agonist isoproterenol. Our results demonstrate that global myocardial in vivo gene delivery is possible and that genetic manipulation of beta-AR density can result in enhanced cardiac performance. Thus, replacement of lost receptors seen in HF may represent novel inotropic therapy.