DNA enzyme targeting TNF-alpha mRNA improves hemodynamic performance in rats with postinfarction heart failure

1  Institute for Nutrition Research and 2  Department of Physiology, University of Oslo, 0316 Oslo; and 3  Department of Immunology, The Norwegian Radium Hospital, 0310 Oslo, Norway Tumor necrosis factor- (TNF- ) probably affects the pathogenesis of heart failure. Here we have investigated the thera...

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Published in:American journal of physiology. Heart and circulatory physiology 2001-11, Vol.281 (5), p.H2211-H2217
Main Authors: Iversen, Per Ole, Nicolaysen, Gunnar, Sioud, Mouldy
Format: Article
Language:English
Subjects:
Animals
Enzymes - chemical synthesis
Enzymes - pharmacology
Heart Failure - drug therapy
Heart Failure - physiopathology
Hemodynamics
Male
Myocardial Infarction - drug therapy
Myocardial Infarction - physiopathology
Rats
Rats, Wistar
RNA, Messenger - metabolism
Transfection
Tumor Necrosis Factor-alpha - genetics
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Summary:1  Institute for Nutrition Research and 2  Department of Physiology, University of Oslo, 0316 Oslo; and 3  Department of Immunology, The Norwegian Radium Hospital, 0310 Oslo, Norway Tumor necrosis factor- (TNF- ) probably affects the pathogenesis of heart failure. Here we have investigated the therapeutic potential of a nuclease-resistant DNA enzyme that specifically cleaves TNF- mRNA. A phosphorothioate-modified DNA enzyme was designed to retain similar cleavage activity as its unmodified version, and that inhibited the expression of TNF- 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- in coronary sinus blood was markedly lowered on treatment, and myocardial TNF- 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. cytokine; gene inactivation; myocardial infarction
ISSN:0363-6135
1522-1539
DOI:10.1152/ajpheart.2001.281.5.h2211