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.
Mehta
J L
JL
Departments of Medicine and Physiology, University of Florida College of Medicine, Florida, USA. HavelkaMarcyJ#exchange.uams.edu
Chen
H
H
Li
D
D
Phillips
I M
IM
D000818:Animals; D015153:Blotting, Western; D006321:Heart / Q000502:physiology; D008297:Male; D009206:Myocardium / Q000201:enzymology*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D010477:Perfusion; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation
D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D013482:Superoxide Dismutase; D007703:Peptidyl-Dipeptidase A