Modulation of Myocardial SOD and iNOS During Ischemia–reperfusion by Antisense Directed at ACE mRNA

Renin–angiotensin system (RAS) is involved in the regulation of superoxide dismutase (SOD) and nitric oxide (NO) equilibrium, and its modulation protects hearts from ischemic dysfunction. We examined the effect of a new antisense-oligodeoxynucleotides (AS-ODNs) directed at ACE mRNA on SOD and iNOS expression during myocardial ischemia. Sprague–Dawley rats were treated with saline, AS-ODNs, or inverted-ODNs (IN-ODNs), given with liposome DOTAP/DOPE. Hearts were excised and subjected to 25 min of ischemia followed by 30 min of reperfusion. Ischemia–reperfusion in saline-treated hearts resulted in a decrease in the expression of SOD and an increase in the expression of inducible NOS (iNOS) genes concurrently with myocardial dysfunction. AS-ODNs, but not IN-ODNs, protected hearts against functional deterioration, and upregulated SOD expression and inhibited the expression of iNOS. ACE protein expression was decreased in the rat hearts of the AS-ODNs-treated group, but not in the IN-ODNs group. Thus manipulation of RAS with AS-ODNs directed at ACE mRNA can ameliorate cardiac dysfunction and modulate expression of SOD and iNOS at genomic level.