Gene therapy strategy for long-term myocardial protection using adeno-associated virus-mediated delivery of heme oxygenase gene
Gene therapy strategy for long-term myocardial protection using adeno-associated virus-mediated delivery of heme oxygenase gene
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DOI：
10.1161/hc0502.103363
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发表时间：
2002-02-05
期刊：
影响因子：
37.8
通讯作者：
Dzau, VJ
中科院分区：
文献类型：
--
作者：
Melo, LG;Agrawal, R;Dzau, VJ
缺血和氧化应激是组织损伤的主要机制。预防性/保护性治疗的理想策略是开发一种方法，该方法可以赋予长期的转基因表达，从而通过单次施用治疗性基因来保护组织免受反复缺血/再灌注损伤。在本研究中，我们使用重组腺相关病毒（rAAV）作为载体直接交付的细胞保护基因血红素加氧酶-1（HO-1）到大鼠心肌，与评估这一战略作为一种治疗方法，长期保护缺血诱导的心肌injuries.Methods和Results-Human HO-1基因（hHO-1）被交付到正常大鼠心脏心肌内注射。在急性冠状动脉结扎和释放前8周，AAV介导的hHO-1基因转移导致左心室心肌梗死的显著减少（>75%）。梗死面积的减少伴随着心肌脂质过氧化和促凋亡Bax和促炎性白细胞介素-1 β蛋白丰度的减少，伴随着抗凋亡Bcl-2蛋白水平的增加。这表明，转基因发挥其心脏保护作用的一部分，通过减少氧化应激和相关的炎症和凋亡细胞death. Conclusions，这项研究记录了有益的治疗效果的rAAV介导的转移，心肌损伤前，细胞保护基因，赋予长期的心肌保护缺血/再灌注损伤。我们的数据表明，这种新的“事件前”基因转移方法可以提供持续的组织保护，防止未来重复发生的损伤，并可能是有益的预防性治疗患者或有风险的发展冠状动脉缺血性事件。
Background-Ischemia and oxidative stress are the leading mechanisms for tissue injury. An ideal strategy for preventive/protective therapy would be to develop an approach that could confer long-term transgene expression and, consequently, tissue protection from repeated ischemia/reperfusion injury with a single administration of a therapeutic gene. In the present study, we used recombinant adeno-associated virus (rAAV) as a vector for direct delivery of the cytoprotective gene heme oxygenase-1 (HO-1) into the rat myocardium, with the purpose of evaluating this strategy as a therapeutic approach for long-term protection from ischemia-induced myocardial injury.Methods and Results-Human HO-1 gene (hHO-1) was delivered to normal rat hearts by intramyocardial injection. AAV-mediated transfer of the hHO-1 gene 8 weeks before acute coronary artery ligation and release led to a dramatic reduction (>75%) in left ventricular myocardial infarction. The reduction in infarct size was accompanied by decreases in myocardial lipid peroxidation and in proapoptotic Bax and proinflammatory interleukin-1beta protein abundance, concomitant with an increase in antiapoptotic Bcl-2 protein level. This suggested that the transgene exerts its cardioprotective effects in part by reducing oxidative stress and associated inflammation and apoptotic cell death.Conclusions-This study documents the beneficial therapeutic effect of rAAV-mediated transfer, before myocardial injury, of a cytoprotective gene that confers long-term myocardial protection from ischemia/reperfusion injury. Our data suggest that this novel "pre-event" gene transfer approach may provide sustained tissue protection from future repeated episodes of injury and may be beneficial as preventive therapy for patients with or at risk of developing coronary ischemic events.