Chronic recurrent myocardial ischemic injury is significantly attenuated by pre-emptive adeno-associated virus heme oxygenase-1 gene delivery
Chronic recurrent myocardial ischemic injury is significantly attenuated by pre-emptive adeno-associated virus heme oxygenase-1 gene delivery
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DOI：
10.1016/j.jacc.2005.09.038
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发表时间：
2006-02-07
影响因子：
24
通讯作者：
Dzau, VJ
中科院分区：
文献类型：
--
作者：
Pachori, AS;Melo, LG;Dzau, VJ
目的：我们对以下假设进行了评估，即抗氧化酶血红素加氧酶 - 1（HO - 1）的过表达可能预防慢性反复缺血/再灌注损伤。
背景：多次反复发生的心肌缺血可导致严重的心肌损伤，包括心肌细胞死亡、纤维化以及心室壁变薄，进而导致心室功能受损和心力衰竭。
方法：在本研究中，我们使用一种慢性反复心肌缺血和再灌注的闭胸啮齿动物模型，以腺相关病毒（AAV） - 2作为递送载体，研究预防性基因治疗在过表达抗氧化酶HO - 1方面的功效。
结果：我们表明，HO - 1的组成性过表达能够预防由反复短暂心肌缺血和再灌注损伤所诱导的心肌壁变薄、炎症、纤维化以及心功能恶化（通过超声心动图、组织学和免疫组织化学检测）。通过HO - 1治疗，根据存活蛋白标志物水平和脱氧核糖核苷酸末端转移酶介导的dUTP缺口末端标记染色确定，细胞凋亡显著减少。这种对组织损伤的预防还与超氧化物产生的减少有关。
结论：综上所述，我们首次提供了预防性AAV - HO - 1递送对预防多次缺血性损伤的治疗功效的证据。这种方法通过同时激活保护反应和抑制病理性左心室重构来保护心肌细胞，因此，对于反复心肌缺血高风险的冠状动脉疾病患者可能是一种有用的心脏保护策略。
OBJECTIVES We assessed the hypothesis that overexpression of the antioxidant enzyme heme oxygenase (HO)-1 may protect against chronic recurrent ischemia/reperfusion injury.BACKGROUND Multiple and recurring episodes of myocardial ischemia can result in significant myocardial damage, including myocyte death, fibrosis, and wall thinning, leading to impaired ventricular function and cardiac failure.METHODS In this study we used a closed-chest rodent model of chronic recurring myocardial ischemia and reperfusion to investigate the efficacy of pre-emptive gene therapy in overexpressing the antioxidant enzyme HO-1, using adeno-associated virus (AAV)-2 as the delivery vector.RESULTS We show that constitutive overexpression of HO-1 can prevent myocardial wan thinning, inflammation, fibrosis, and deterioration of cardiac function (as measured by echocardiography, histology, and immunohistochemistry) induced by repeated transient myocardial ischemia and reperfusion injury. With HO-1 therapy, there was a significant reduction in apoptosis as determined by levels of markers of survival proteins and terminal deoxynucleotidyltransferase dUTP nick end-labeling staining. This prevention of tissue damage was also associated with reduction in superoxide generation.CONCLUSIONS Taken together we provide the first evidence of the therapeutic efficacy of pre-emptive AAV-HO-1 delivery for prevention against multiple ischemic injury. This approach protects myocytes by simultaneously activating protective response and inhibiting pathological left ventricular remodeling and, therefore, may be a useful cardio-protective strategy for patients with coronary artery disease at a high risk for recurrent myocardial ischemia.