DNA enzyme targeting TNF-α mRNA improves hemodynamic performance in rats with postinfarction heart failure
DNA enzyme targeting TNF-α mRNA improves hemodynamic performance in rats with postinfarction heart failure
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DOI：
10.1152/ajpheart.2001.281.5.h2211
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发表时间：
2001-11-01
影响因子：
4.8
通讯作者：
Sioud, M
中科院分区：
文献类型：
--
作者：
Iversen, PO;Nicolaysen, G;Sioud, M
肿瘤坏死因子- α (tnf - α)可能影响心力衰竭的发病机制。在这里，我们研究了一种抗核酸酶的DNA酶的治疗潜力，这种酶可以特异性地切割tnf - α mRNA。设计了一种硫代修饰的DNA酶，使其保持与未修饰的DNA酶相似的裂解活性，并在体外抑制tnf - α的表达。为验证其在体内的作用，采用麻醉大鼠左冠状动脉结扎法诱导梗死后充血性心力衰竭。与对照组相比，DNA酶治疗4周后，左心室舒张末压和肺重量显著降低，同时动脉血压和心肌血流量增加。冠脉窦血tnf - α浓度明显降低，心肌tnf - α mRNA显著降低。恢复研究表明，在观察期间心肌内存在DNA酶裂解活性，无明显毒性作用。我们的研究结果表明，基于DNA酶的疗法可能在治疗这种使人衰弱的疾病方面有希望。
Tumor necrosis factor-alpha (TNF-alpha) probably affects the pathogenesis of heart failure. Here we have investigated the therapeutic potential of a nuclease-resistant DNA enzyme that specifically cleaves TNF-alpha mRNA. A phosphorothioate-modified DNA enzyme was designed to retain similar cleavage activity as its unmodified version, and that inhibited the expression of TNF-alpha in vitro. To test its efficacy in vivo, postinfarction congestive heart failure was induced in anesthetized rats by ligation of the left coronary artery. A 4-wk treatment with the DNA enzyme induced a substantial reduction in left ventricular end-diastolic pressure and lung weight concomitant with an increase in arterial blood pressure and myocardial blood flow compared with controls. The concentration of TNF-alpha in coronary sinus blood was markedly lowered on treatment, and myocardial TNF-alpha mRNA was substantially reduced. Recovery studies showed that the DNA enzyme cleavage activity was present within the myocardium throughout the observation period and had no apparent toxic effects. Our findings indicate that DNA enzyme-based therapy may hold promise in the treatment of this debilitating disease.