Adeno-associated Virus Serotype 9 - Driven Expression of BAG3 Improves Left Ventricular Function in Murine Hearts with Left Ventricular Dysfunction Secondary to a Myocardial Infarction.
Adeno-associated Virus Serotype 9 - Driven Expression of BAG3 Improves Left Ventricular Function in Murine Hearts with Left Ventricular Dysfunction Secondary to a Myocardial Infarction.
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DOI：
10.1016/j.jacbts.2016.08.008
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发表时间：
2016-12
期刊：
影响因子：
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通讯作者：
Feldman AM
中科院分区：
文献类型：
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作者：
Knezevic T;Myers VD;Su F;Wang J;Song J;Zhang XQ;Gao E;Gao G;Muniswamy M;Gupta MK;Gordon J;Weiner KN;Rabinowitz J;Ramsey FV;Tilley DG;Khalili K;Cheung JY;Feldman AM
BAG3是一种高度保守的蛋白，具有多效性，在心脏、骨骼肌和许多癌症中高水平表达。BAG3水平在许多形式的左冠状动脉功能障碍中降低，包括结扎左冠状动脉后的小鼠。在CMV启动子(rAAV9-BAG3)的控制下，将与小鼠BAG3偶联的腺相关病毒(rAAV9-BAG3)后轨道后注射小鼠，可在注射后7天增加心肌BAG3的水平。小鼠心肌梗死后眶后注射rAAV9-BAG3可改善心功能，而无心肌梗死时rAAV9-BAG3对心功能无影响。BAG3可能成为治疗心力衰竭的新靶点。BAG3基因突变与骨骼肌功能障碍和扩张型心肌病有关。眼眶后注射表达BAG3腺相关病毒血清9型(rAAV9-BAG3)显著(p<0.0001)改善了心肌梗死继发心功能障碍小鼠注射后9天的左心室射血分数、短轴缩短率和每搏量。此外，注射后3周分离的小鼠心肌细胞显示细胞缩短，收缩期[Ca~(2+)]_i升高，[Ca~(2+)]_i瞬时幅度增加，最大L型钙电流幅度增大。这些结果表明，BAG3基因治疗可能为心力衰竭的治疗提供一种新的治疗选择。
BAG3 is a highly conserved protein having pleiotropic effects that is expressed at high levels in the heart, skeletal muscles, and many cancers. BAG3 levels are reduced in many forms of LV dysfunction including mice after ligation of the left coronary artery. Retro-orbital injection of mice with an adeno-associated virus coupled to murine BAG3 under the control of a CMV promoter (rAAV9-BAG3) increased myocardial levels of BAG3 by 7 days post-injection. Retro-orbital injection of rAAV9-BAG3 in mice post-myocardial infarction improved LV function, whereas rAAV9-BAG3 had no effect on LV function in the absence of an MI. BAG3 may prove to be a new therapeutic target in the treatment of heart failure. Mutations in Bcl-2–associated athanogene 3 (BAG3) were associated with skeletal muscle dysfunction and dilated cardiomyopathy. Retro-orbital injection of an adeno-associated virus serotype 9 expressing BAG3 (rAAV9-BAG3) significantly (p < 0.0001) improved left ventricular ejection fraction, fractional shortening, and stroke volume 9 days post-injection in mice with cardiac dysfunction secondary to a myocardial infarction. Furthermore, myocytes isolated from mice 3 weeks after injection showed improved cell shortening, enhanced systolic [Ca2+]i and increased [Ca2+]i transient amplitudes, and increased maximal L-type Ca2+ current amplitude. These results suggest that BAG3 gene therapy may provide a novel therapeutic option for the treatment of heart failure.