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Protection against myocardial dysfunction induced by global ischemia-reperfusion by antisense-oligodeoxynucleotides
1Department of Medicine, University of Florida College of Medicine, Gainesville 32610, USA.
Abstract:
Plasma catecholamine levels rise, and myocardial beta(1)-adrenoceptor (beta(1)-AR) sensitivity increases during ischemia. These factors enhance myocardial injury and cardiac dysfunction. beta(1)-AR blockers are clinically used to protect heart against ischemia and to improve cardiac dysfunction in patients with ischemic heart disease, but these agents often cause intolerable side effects. To examine the potential cardioprotective effect of therapy with antisense-oligodeoxynucleotides directed at beta(1)-AR mRNA (beta(1)-AS-ODNs) during myocardial ischemia-reperfusion, Sprague-Dawley rats were treated with beta(1)-AS-ODNs or inverted-oligodeoxynucleotides (IN-ODNs), each 200 microg/rat. Hearts were excised, perfused, and subjected to global ischemia (30 min) followed by reperfusion (30 min). Other rats were given selective beta(1)-AR blocker atenolol (2 mg/kg) or saline before excising the hearts. Ischemia-reperfusion resulted in cardiac dysfunction, indicated by an increase in coronary perfusion pressure and left ventricular end-diastolic pressure and a decrease in developed left ventricular pressure, as well as evidence of lipid peroxidation in saline-treated rats (all P <.05 versus control values). Administration of AS-ODNs or atenolol, but not IN-ODNs, protected hearts against functional deterioration and lipid peroxidation (P <.05 versus saline or IN-ODNs treatment). AS-ODNs therapy appeared to be equivalent to atenolol in these effects. Expression of beta(1)-AR protein as well as mRNA in the myocardium were markedly up-regulated after ischemia-reperfusion, and treatment with beta(1)-AS-ODNs, but not atenolol, decreased the rise in enhanced expression of beta(1)-AR. These observations imply that beta(1)-AS-ODNs can ameliorate cardiac dysfunction after ischemia-reperfusion by reducing the expression of beta(1)-AR in the ischemic-reperfused myocardium.
Insights
Antisense-oligodeoxynucleotides targeting beta(1)-adrenoceptor mRNA protect the heart from ischemia-reperfusion injury, offering an alternative to beta-blockers. This therapy reduces cardiac dysfunction and lipid peroxidation by downregulating beta(1)-AR expression.
Area of Science:
- Cardiovascular Science
- Molecular Cardiology
- Pharmacology
Background:
- Myocardial ischemia increases plasma catecholamines and beta(1)-adrenoceptor (beta(1)-AR) sensitivity, exacerbating cardiac injury and dysfunction.
- Beta(1)-AR blockers are used for ischemic heart disease but can cause side effects.
- Antisense-oligodeoxynucleotides (AS-ODNs) offer a potential targeted approach to modulate receptor expression.
Purpose of the Study:
- To investigate the cardioprotective effects of beta(1)-AS-ODNs during myocardial ischemia-reperfusion.
- To compare the efficacy of beta(1)-AS-ODNs with a selective beta(1)-AR blocker, atenolol.
Main Methods:
- Rats were treated with beta(1)-AS-ODNs, inverted-oligodeoxynucleotides (IN-ODNs), atenolol, or saline.
- Hearts underwent 30 minutes of global ischemia followed by 30 minutes of reperfusion.
- Cardiac function and lipid peroxidation were assessed.
Main Results:
- Ischemia-reperfusion caused cardiac dysfunction and lipid peroxidation in saline-treated rats.
- Both beta(1)-AS-ODNs and atenolol administration protected hearts against functional deterioration and lipid peroxidation.
- Beta(1)-AS-ODNs, but not atenolol, reduced the upregulation of beta(1)-AR mRNA and protein expression.
Conclusions:
- Beta(1)-AS-ODNs demonstrate cardioprotective effects comparable to atenolol in ischemia-reperfusion.
- This therapy ameliorates cardiac dysfunction by reducing beta(1)-AR expression in the ischemic-reperfused myocardium.
- Beta(1)-AS-ODNs represent a promising therapeutic strategy for ischemic heart disease.