Effect of bortezomib on the efficacy of AAV9.SERCA2a treatment to preserve cardiac function in a rat pressure-overload model of heart failure.
Effect of bortezomib on the efficacy of AAV9.SERCA2a treatment to preserve cardiac function in a rat pressure-overload model of heart failure.
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DOI：
10.1038/gt.2014.7
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发表时间：
2014-04
期刊：
影响因子：
5.1
通讯作者：
Weber, T.
中科院分区：
文献类型：
--
作者：
Chaanine, A. H.;Nonnenmacher, M.;Kohlbrenner, E.;Jin, D.;Kovacic, J. C.;Akar, F. G.;Najjar, R. J.;Weber, T.
基于腺相关病毒（AAV）的载体是用于治疗性基因递送（包括用于治疗心力衰竭）的有前景的载体。已经证明，对于AAV血清型1至8中的每一种，蛋白酶体的抑制导致转导效率增加。然而，对于AAV 9，蛋白酶体抑制剂对体内转导的影响迄今尚未被评估。在此，我们证明，在完善的啮齿动物心力衰竭模型中，用蛋白酶体抑制剂硼替佐米同时治疗不会增强AAV9.SERCA2a改善心脏功能的功效，如通过超声心动图和压力容积分析所检查的。SERCA 2a蛋白的Western印迹分析和SERCA 2a mRNA的RT-PCR证明硼替佐米对内源性大鼠SERCA 2a水平和由AAV9.SERCA2a递送的人SERCA 2a的表达水平均没有影响。类似地，心脏样品中AAV 9基因组的数量不受硼替佐米处理的影响。有趣的是，尽管AAV 9对HeLa细胞和新生大鼠心肌细胞的转导被刺激，但对成年大鼠心肌细胞的转导被抑制。这些结果表明蛋白酶体抑制对AAV 9转导的器官/细胞类型特异性作用。未来对潜在分子机制的详细分析有望促进改进AAV载体的开发。
Adeno-associated virus (AAV)-based vectors are promising vehicles for therapeutic gene delivery, including for the treatment of heart failure. It has been demonstrated for each of the AAV serotypes 1 through 8 that inhibition of the proteasome results in increased transduction efficiencies. For AAV9, however, the effect of proteasome inhibitors on in vivo transduction has until now not been evaluated. Here we demonstrate, in a well-established rodent heart failure model, that concurrent treatment with the proteasome inhibitor bortezomib does not enhance the efficacy of AAV9.SERCA2a to improve cardiac function as examined by echocardiography and pressure volume analysis. Western blot analysis of SERCA2a protein and RT-PCR of SERCA2a mRNA demonstrated that bortezomib had no effect on either endogenous rat SERCA2a levels nor on expression levels of human SERCA2a delivered by AAV9.SERCA2a. Similarly, the number of AAV9 genomes in heart samples was unaffected by bortezomib treatment. Interestingly, whereas transduction of HeLa cells and neonatal rat cardiomyocytes by AAV9 was stimulated, transduction of adult rat cardiomyocytes was inhibited. These results indicate an organ/cell-type specific effect of proteasome inhibition on AAV9 transduction. A future detailed analysis of the underlying molecular mechanisms promises to facilitate the development of improved AAV vectors.
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影响因子：
37.8
作者：
del Monte, F;Williams, E;Hajjar, RJ
通讯作者：
Hajjar, RJ
影响因子：
64.8
作者：
Kho, Changwon;Lee, Ahyoung;Jeong, Dongtak;Oh, Jae Gyun;Chaanine, Antoine H.;Kizana, Eddy;Park, Woo Jin;Hajjar, Roger J.
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Hajjar, Roger J.
影响因子：
37.8
作者：
BAAN, J;VANDERVELDE, ET;BUIS, B
通讯作者：
BUIS, B
影响因子：
5.1
作者：
Dalkara, D.;Byrne, L. C.;Flannery, J. G.
通讯作者：
Flannery, J. G.
影响因子：
--
作者：
Kohlbrenner, Erik;Henckaerts, Els;Weber, Thomas
通讯作者：
Weber, Thomas