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Protection against ischemia/reperfusion injury and myocardial dysfunction by antisense-oligodeoxynucleotide directed at angiotensin-converting enzyme mRNA

Gene Therapy volume 8, pages 804–810 (2001)Cite this article

Abstract

Angiotensin-converting enzyme (ACE) activity in the myocardium and angiotensin-II (Ang-II) levels in plasma increase after myocardial ischemia, which lead to exacerbation of myocardial injury and cardiac dysfunction. We examined the protective role of novel antisense-oligodeoxynucleotide (AS-ODN) directed at ACE mRNA in myocardial ischemic injury. Sprague–Dawley rats were treated with ACE-AS-ODN (200 μg per rat, n = 8, i.v.) or inverted-ODN (IN-ODN, 200 μg per rat, n = 8, i.v.), given with 600 μg per rat of liposome DOTAP/DOPE. Hearts from AS-ODN- or IN-ODN-treated rats were excised, perfused in vitro, and subjected to 25 min of global ischemia followed by 30 min of reperfusion. Parallel groups of rats were given ACE inhibitor captopril (5 mg/kg, n = 8) or saline (n = 8) before excising the hearts. Ischemia/reperfusion resulted in myocardial dysfunction (increase in coronary perfusion pressure and LV end-diastolic pressure and a decrease in developed LV pressure) in the saline-treated rats. Myocardial dysfunction was associated with evidence of lipid peroxidation and enzyme leakage (MDA and LDH levels in the myocardium) and up-regulation of ACE protein expression. Administration of AS-ODN or captopril, but not IN-ODN, reduced Ang-II levels in the plasma, decreased ischemia/reperfusion-mediated cardiac functional deterioration and lipid peroxidation, and preserved LDH in the myocardium (all P < 0.05 versus the saline group). AS-ODN and captopril had equipotent effects on cardiac dynamics. ACE protein expression (western blot) was decreased in the hearts of the AS-ODN-treated group, but not in IN-ODN-treated rat hearts. In contrast, ACE protein expression was significantly increased in captopril-treated rat hearts. These observations suggest that AS-ODN directed at ACE mRNA can ameliorate myocardial dysfunction and injury after ischemia/reperfusion, and its use is associated with decreased expression of ACE protein in the ischemic myocardium.

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Acknowledgements

This work was supported by grants from the Veterans Affairs and the Department of Defense and a MERIT Award from the National Institutes of Health.

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Authors and Affiliations

  1. Department of Medicine and Physiology, University of Arkansas and VA Medical Center, Little Rock, AR, USA

    H Chen, D Li, P Mehta & J L Mehta

  2. Department of Physiology, University of Florida College of Medicine, Gainesville, FL, USA

    D Mohuczy, B Kimura & M I Phillips

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Chen, H., Mohuczy, D., Li, D. et al. Protection against ischemia/reperfusion injury and myocardial dysfunction by antisense-oligodeoxynucleotide directed at angiotensin-converting enzyme mRNA. Gene Ther 8, 804–810 (2001). https://doi.org/10.1038/sj.gt.3301439

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