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Antiarrhythmic effects of ceruloplasmin during reperfusion in the ischemic isolated rat heart
R Atanasiu1, M J Dumoulin, R Chahine
1Department of Physiology, Université de Montréal, Hôpital du Sacré-Coeur de Montréal, Canada.
Insights
Ceruloplasmin, a serum antioxidant, protects isolated rat hearts from reperfusion arrhythmias. Its cardioprotective effect depends on both dose and molecular integrity, offering a promising therapeutic avenue.
Area of Science:
- Cardiovascular Research
- Biochemistry
- Pharmacology
Background:
- Reperfusion arrhythmias pose a significant risk following ischemic events.
- Ceruloplasmin is a key serum antioxidant with potential cardioprotective properties.
- Understanding ceruloplasmin's role in cardiac protection is crucial for developing new therapeutic strategies.
Purpose of the Study:
- To investigate the cardioprotective effects of ceruloplasmin against reperfusion-induced arrhythmias in isolated rat hearts.
- To determine the dose-response relationship of ceruloplasmin in preventing ventricular fibrillation.
- To assess the importance of ceruloplasmin's conformational integrity for its cardioprotective activity.
Main Methods:
- Isolated rat hearts were subjected to regional ischemia followed by reperfusion.
- Ceruloplasmin of varying concentrations and conformational integrity was administered prior to reperfusion.
- Deferoxamine served as a positive control, while inactivated ceruloplasmin and albumin acted as negative controls.
Main Results:
- Ceruloplasmin significantly reduced the incidence of total and irreversible ventricular fibrillation in a dose-dependent and molecular integrity-dependent manner.
- The protective effect of ceruloplasmin was observed at much lower concentrations compared to deferoxamine.
- Inactivated or denatured ceruloplasmin and albumin did not exhibit any protective effects against reperfusion arrhythmias.
Conclusions:
- Ceruloplasmin demonstrates significant cardioprotection against reperfusion arrhythmias in a clinically relevant model.
- The study highlights the critical role of ceruloplasmin's molecular integrity in its antioxidant and antiarrhythmic functions.
- Ceruloplasmin represents a potential therapeutic agent for mitigating cardiac damage post-ischemia.
Abstract:
The ability of ceruloplasmin, an important serum antioxidant, to reduce the vulnerability of the isolated rat heart to reperfusion arrhythmias has been investigated. Bovine plasma ceruloplasmin was purified by chromatography on aminoethyl-agarose. Isolated rat hearts were submitted to 15 min of regional ischemia and 10 min of reperfusion. The dose-effect relationship and the role of ceruloplasmin conformational integrity in cardioprotection were established by treatment of ischemic hearts with ceruloplasmin at various concentrations (0.25, 0.5, 1, and 2 microM) and at different degrees of conformational integrity (A610/A280 = 0.02, 0.04, and 0.06), 5 min before reperfusion. Deferoxamine (20-500 microM) was used as a positive control. As negative controls we used chemically inactivated ceruloplasmin (1 microM), heat-denatured ceruloplasmin (1 microM), and albumin (1-4 microM). In the control group during the first 5 min of reperfusion, the incidence of total ventricular fibrillation was 100% and of irreversible ventricular fibrillation was 83%. The incidence of reversible and irreversible ventricular fibrillation was significantly decreased in the ceruloplasmin-treated groups in both a dose and molecular integrity dependent manner. Ceruloplasmin had no effect on the incidence of ventricular tachycardia. Deferoxamine reduced the incidence of ventricular fibrillation to the same degree as ceruloplasmin but at concentrations much higher than those of ceruloplasmin. Chemically inactivated ceruloplasmin, heat-denatured ceruloplasmin, and albumin had no protective effects on reperfusion-induced arrhythmias.