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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 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
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