Myocardial ischemia protection by HO-1 gene delivery

描述(申请人提供)：心肌缺血引起炎症 反应、心功能下降和不可逆转的细胞死亡。形成 缺血区再灌流后的ROS升高 对缺血儿的侮辱。受损的细胞对这种侮辱的反应是激活血红素 加氧酶-1(HO-1)酶，提供细胞保护作用。近期 有证据表明，事先诱导HO-1可以保护组织免受 缺血/再灌注(I/R)介导损伤，延长组织存活时间。 因此，HO-1的靶向过表达是可能的 无压力的条件将防止未来的侮辱，并提供进一步的 了解HO-1？S的保护机制。我们最近开发了一种 腺相关病毒载体系统直接携带人HO-1基因 大鼠心脏，并长期观察到转基因和 一次病毒载体治疗可减少心肌梗死面积 冠状动脉结扎(LAD)缺血/再灌注模型。这项建议 将检验这样的假设，即心内注射HHO-1将导致 HHO-1的长期转录和翻译，提供细胞保护 LAD模型改善心脏血流动力学和降低总死亡率的作用 I/R损伤。

DESCRIPTION (provided by applicant): Myocardial ischemia causes inflammatory response, reduced cardiac function and irreversible cell death. Formation of reactive oxygen species (ROS) upon reperfusion of the ischemic area augments the ischemic insult. Injured cells respond to this insult by activating heme oxygenase-1 (HO-1) enzyme, which provides cytoprotective effects. Recent evidence has shown that prior induction of HO-1 protects tissues against ischemia/reperfusion (I/R) mediated injury and prolongs tissue viability. Therefore it is possible that targeted overexpression of HO-1 under non-stressful conditions will protect against future insult and provide further understanding of HO-1?s protective mechanisms. We have recently developed an adeno-associated viral vector system to deliver human HO-1 (hHO-1) directly in the rat heart and have observed long term expression of the transgene and reduction in infarct size with a single treatment of the viral vector in a coronary artery ligation (LAD) model of ischemia/reperfusion. This proposal will test the hypothesis that intracardiac delivery of hHO-1 will result in long term transcription and translation of hHO-1, provide cytoprotective effects improve cardiac hemodynamics and reduce overall mortality in LAD model of I/R injury.