A novel gene therapy for congestive heart failure.

β-肾上腺素能受体系统在心脏收缩中起着重要作用。如果在受体下调的心脏中，外源性给药能增加受体，这种方法可能会改善心功能。为验证通过缩窄腹主动脉将β2肾上腺素能受体(B2AR)基因导入正常心脏和衰竭心脏是否具有改善心功能的作用，采用冠状动脉内注入日本血凝病毒(HVJ)-含人B2AR基因的脂质体复合体(bar(+)和pBAR(+)组)的方法，在SD大鼠心脏内导入B2AR基因的c DNA。对照组注入不含受体基因的HVJ-脂质体复合体(bar(-)和pBAR(-)组)。4天后，对心脏进行检查。用人B2AR特异性抗体进行免疫组织化学标记，BAR(+)组和pBAR(+)组的肌膜标记良好，而BAR(-)和pBAR(-)组的肌膜标记较差。[~(125)I]-氰基吲哚配基结合实验显示，BAR(+)和pBAR(+)组心脏的受体密度明显高于BAR(-)和pBAR(-)组。采用朗宁多夫系统评价，异丙肾上腺素注射后，BAR(+)组和pBAR(+)组的左心室显影压力和最大导数显著高于BAR(-)和pBAR(-)组。注射异丙肾上腺素后，BAR(+)和pBAR(+)组的左心室最小导数显著低于BAR(-)和pBAR(-)组。结果表明，在正常大鼠心脏和心力衰竭大鼠心脏中，通过注射异丙肾上腺素后，通过体内基因转染法获得的β2肾上腺素能受体高表达约4倍，并且心脏反应明显增强。

Beta adrenergic receptor system has a major important role in cardiac contraction. If the receptor can be increased by exogenous administration in the hearts in which the receptor is downregulated, this approach may improve the cardiac function. To test whether in-vivo gene transfection of beta 2 adrenergic receptor (B2AR) into the normal and the failing heart by constriction of the abdominal aorta can enhance cardiac function, we transfected with cDNA of the receptor in the heart of Sprague-Dawley rat by intracoronary infusion of hemaagglutinating virus of Japan (HVJ) -liposome plasmid complex including human B2AR gene (BAR (+) and pBAR (+) group). Control hearts were infused with HVJ-liposome plasmid complex without the receptor gene (BAR (-) and pBAR (-) group). Four days after transfection, the hearts were examined. Immunohistochemical labeling using specific antibody to human B2AR demonstrated that the sarcolemma of the myocytes in BAR (+) and pBAR (+) groups was well labeled, while anywhere in BAR (-) and pBAR (-) groups was not. Ligand binding assay using [125I] -cyanopindolol revealed that the receptor density of the hearts in BAR (+) and pBAR (+) groups was significantly higher than in BAR (-) and pBAR (-) groups. Evaluation using Langendorff system demonstrated that developed pressure and maximum derivative of the left ventricle after infusion of isoproterenol were significantly higher in BAR (+) and pBAR (+) groups than in BAR(-) and pBAR (-) groups. Minimum derivative of the left ventricle after infusion of isoproterenol was significantly lower in BAR (+) and pBAR (+) groups than in BAR (-) and pBAR (-) groups. Our results indicated that beta 2 adrenergic receptor was overexpressed approximately 4 times in normal rat hearts and the failing heart by pressure overload by in-vivo gene transfection using HVJ liposome method and the transfected hearts demonstrated marked enhancements in cardiac response after infusion of isoproterenol.