多基因腺病毒疗法用于减轻心脏移植保存后缺血再灌注损伤

Multigene adenoviral therapy for the attenuation of ischemia-reperfusion injury after preservation for cardiac transplantation.

作者信息

Abunasra Haitham J, Smolenski Ryszard T, Yap John, Sheppard Mary, O'Brien Timothy, Yacoub Magdi H

机构信息

Heart Science Centre, Imperial College at Harefield Hospital, Harefield, United Kingdom.

出版信息

J Thorac Cardiovasc Surg. 2003 May;125(5):998-1006. doi: 10.1067/mtc.2003.263.

DOI:10.1067/mtc.2003.263

PMID:12771872

Abstract

OBJECTIVE

The protective effect of adenovirus-mediated ex vivo multigene transfer with superoxide dismutase, a free radical scavenger, and nitric oxide, a vasodilator with anti-inflammatory properties, was examined in the rat heart during experimental ischemia-reperfusion mimicking preservation for cardiac transplantation.

METHODS

Donor rat hearts (n = 6 per group) were perfused with solution containing adenoviral vector carrying genes for beta-galactosidase (group A), endothelial nitric oxide synthase (group B), manganese superoxide dismutase (group C), or both endothelial nitric oxide synthase and manganese superoxide dismutase (group D). Hearts were then implanted heterotopically into the abdomens of recipient rats. Four days later, transplanted hearts were collected, connected to a Langendorff perfusion apparatus, and subjected to 6 hours of ischemia followed by 1 hour of reperfusion. Cardiac function was evaluated with an intraventricular balloon at the beginning of Langendorff perfusion and after ischemia-reperfusion.

RESULTS

Effective gene transfection was confirmed with X-gal staining in group A hearts. Positive immunoreactivity for endothelial nitric oxide synthase, manganese superoxide dismutase, or both was present predominantly in cardiomyocytes in group B, C, and D hearts. Percentage recovery of preischemic left ventricular developed pressure was 62.1% +/- 7.36% in group A; recoveries were increased to 79.6% +/- 6.4%, 86.8% +/- 9.1%, and 79.4% +/- 6.2% in groups B, C, and D, respectively.

CONCLUSION

These results indicate that adenoviral gene transfer of manganese superoxide dismutase and endothelial nitric oxide synthase can attenuate myocardial ischemia-reperfusion injury, with the former providing the most significant protection. Combined overexpression of manganese superoxide dismutase and endothelial nitric oxide synthase did not enhance myocardial recovery any further.

摘要

目的

在模拟心脏移植保存的实验性缺血再灌注过程中，研究腺病毒介导的超氧化物歧化酶（一种自由基清除剂）和一氧化氮（一种具有抗炎特性的血管舒张剂）体外多基因转移对大鼠心脏的保护作用。

方法

用含有携带β-半乳糖苷酶基因的腺病毒载体的溶液灌注供体大鼠心脏（每组n = 6）（A组）、内皮型一氧化氮合酶基因的溶液（B组）、锰超氧化物歧化酶基因的溶液（C组）或同时含有内皮型一氧化氮合酶和锰超氧化物歧化酶基因的溶液（D组）。然后将心脏异位植入受体大鼠腹部。4天后，收集移植心脏，连接到Langendorff灌注装置，进行6小时缺血，随后1小时再灌注。在Langendorff灌注开始时和缺血再灌注后，用室内球囊评估心脏功能。

结果

A组心脏经X-gal染色证实基因有效转染。B组、C组和D组心脏中，内皮型一氧化氮合酶、锰超氧化物歧化酶或两者的阳性免疫反应主要存在于心肌细胞中。A组缺血前左心室舒张末压的恢复百分比为62.1%±7.36%；B组、C组和D组的恢复率分别提高到79.6%±6.4%、86.8%±9.1%和79.4%±6.2%。