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Effects of different preproendothelin-1 mRNA anti-sense oligodeoxynucleotides on ischemic arrhythmias in rats
1Department of Physiology, College of Basic Medical Sciences, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, People's Republic of China.
Abstract:
The effects of four anti-sense oligodeoxynucleotides (AS-ODNs) against rat or human preproendothelin-1 mRNA on ischemic arrhythmias in anesthetized rats were studied. AS-ODN (60 nmol/kg) or control (normal saline; sense-ODN, and scrambled-ODN, 60 nmol/kg) was injected 2 h before acute myocardial ischemia elicited by the occlusion of the left anterior descending coronary artery. Arrhythmias during 60-min ischemia were assessed, and plasma endothelin-1 was determined with an endothelin-1-specific radioimmunoassay system. The results showed that anti-senses against human preproendothelin-1 mRNA were anti-arrhythmic without significant impact on hemodynamics, whereas two against rat preproendothelin-1 mRNA and the three controls failed to be anti-arrhythmic. In human antisense groups, both the incidence of reversible ventricular fibrillation and the mortality were decreased to zero. The incidences of ventricular tachycardia and salvos were significantly decreased from almost 100% in the controls to < or =30% (p < 0.01), the arrhythmia score from an average of approximately 3.6 to 0 and 0.7, respectively (p < 0.01 versus controls), and the total ventricular ectopic beats from an average of 307-338 to < 40 (p < 0.01). The human AS-ODNs led to less plasma endothelin-1, which was associated with suppressed ischemic arrhythmias in this rat model, indicating a contributory role of endothelin-1 in ischemic arrhythmias. Conversely, considering the two- or three-base mismatches between the human AS-ODNs and rat preproendothelin-1 mRNA, and the failure of the rat AS-ODNs in suppressing arrhythmias, the possibility could not be excluded that human endothelin-1 AS-ODNs acted via an undetermined pathway other than endothelin-1.
Insights
Anti-sense oligodeoxynucleotides targeting human preproendothelin-1 mRNA reduced ischemic arrhythmias in rats. These findings suggest endothelin-1 plays a role in arrhythmias, though alternative pathways may exist.
Area of Science:
- Cardiovascular Pharmacology
- Molecular Biology
- Ischemic Heart Disease Research
Background:
- Endothelin-1 is implicated in cardiovascular regulation and disease.
- Ischemic arrhythmias pose a significant threat following myocardial infarction.
- Anti-sense oligodeoxynucleotides (AS-ODNs) offer a targeted approach to gene silencing.
Purpose of the Study:
- To investigate the anti-arrhythmic effects of AS-ODNs against preproendothelin-1 mRNA in a rat model of acute myocardial ischemia.
- To determine the role of endothelin-1 in the development of ischemic arrhythmias.
- To compare the efficacy of AS-ODNs targeting rat versus human preproendothelin-1 mRNA.
Main Methods:
- Administered AS-ODNs or control solutions (saline, sense-ODN, scrambled-ODN) to anesthetized rats 2 hours before inducing myocardial ischemia.
- Assessed arrhythmias during 60 minutes of ischemia by occluding the left anterior descending coronary artery.
- Quantified plasma endothelin-1 levels using radioimmunoassay.
Main Results:
- AS-ODNs targeting human preproendothelin-1 mRNA significantly reduced ischemic arrhythmias, including ventricular fibrillation and tachycardia, with zero mortality.
- AS-ODNs against rat preproendothelin-1 mRNA and all control treatments failed to demonstrate anti-arrhythmic effects.
- Human AS-ODN treatment lowered plasma endothelin-1 levels, correlating with suppressed arrhythmias, suggesting endothelin-1's contribution.
Conclusions:
- AS-ODNs targeting human preproendothelin-1 mRNA exhibit significant anti-arrhythmic properties in a rat model of myocardial ischemia.
- Endothelin-1 appears to contribute to the pathogenesis of ischemic arrhythmias.
- Potential off-target effects or alternative mechanisms of action for human AS-ODNs cannot be ruled out due to species-specific mRNA differences.
