In vivo gene delivery of HSP70i by adenovirus and adeno-associated virus preserves contractile function in mouse heart following ischemia-reperfusion
In vivo gene delivery of HSP70i by adenovirus and adeno-associated virus preserves contractile function in mouse heart following ischemia-reperfusion
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DOI：
10.1152/ajpheart.00323.2006
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发表时间：
2006-12-01
影响因子：
4.8
通讯作者：
Dillmann, Wolfgang H.
中科院分区：
文献类型：
--
作者：
Belke, Darrell D.;Gloss, Bernd;Dillmann, Wolfgang H.
诱导型热休克蛋白70（Inducible heat shock protein 70，HSP 70 i）对缺血再灌注心脏具有保护作用。虽然在热休克动物和组成型过表达该蛋白的转基因小鼠中进行了研究，但该蛋白以病毒载体介导的HSP 70 i表达形式的治疗应用尚未得到广泛研究。因此，我们已经检查了通过病毒基因治疗在小鼠中体内递送到心脏的左心室游离壁的HSP 70 i的作用。通过使离体Langendorff灌注的心脏经受缺血-再灌注方案，在小鼠中短期表达（5天腺病毒介导的）和长期表达（8月腺相关病毒介导的）后，检查病毒介导的HSP 70 i表达在缺血-再灌注后保护心脏功能中的作用。两种载体都能够增加心脏中HSP 70 i的表达，并且与相应的对照相比，两种载体在有氧（缺血前）灌注期间对心脏功能没有任何影响。相比之下，腺病毒介导和腺相关病毒介导的HSP 70 i表达均改善了缺血再灌注120分钟后心脏的收缩恢复。本研究证明了使用病毒介导的HSP 70 i的短期和长期表达作为针对心脏缺血再灌注损伤的治疗干预的可行性。
Inducible heat shock protein 70 (HSP70i) has been shown to exert a protective effect in hearts subjected to ischemia-reperfusion. Although studied in heat-shocked animals and in transgenic mice that constitutively overexpress the protein, the therapeutic application of the protein in the form of a viral vector-mediated HSP70i expression has not been widely examined. Accordingly, we have examined the effects of HSP70i delivered in vivo to the left ventricular free wall of the heart via viral gene therapy in mice. The affect of virally mediated HSP70i expression in preserving cardiac function following ischemia-reperfusion was examined after short-term expression (5-day adenovirus mediated) and long-term expression (8-mo adeno-associated virus mediated) in mice by subjecting ex vivo Langendorff perfused hearts to a regime of ischemia-reperfusion. Both vectors were capable of increasing HSP70i expression in the heart, and neither vector had any effect on cardiac function during aerobic (preischemic) perfusion when compared with corresponding controls. In contrast, both adenovirus-mediated and adeno-associated virus-mediated expression of HSP70i improved the contractile recovery of the heart after 120 min of reperfusion following ischemia. This study demonstrates the feasibility of using both short- and long-term expression of virally mediated HSP70i as a therapeutic intervention against cardiac ischemia-reperfusion injury.