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Carvedilol protects against doxorubicin-induced mitochondrial cardiomyopathy
D L Santos1, A J M Moreno, R L Leino
1University of Tras-Os-Montes and Alto Douro, Vila Real, Portugal.
Abstract:
Several cytopathic mechanisms have been suggested to mediate the dose-limiting cumulative and irreversible cardiomyopathy caused by doxorubicin. Recent evidence indicates that oxidative stress and mitochondrial dysfunction are key factors in the pathogenic process. The objective of this investigation was to test the hypothesis that carvedilol, a nonselective beta-adrenergic receptor antagonist with potent antioxidant properties, protects against the cardiac and hepatic mitochondrial bioenergetic dysfunction associated with subchronic doxorubicin toxicity. Heart and liver mitochondria were isolated from rats treated for 7 weeks with doxorubicin (2 mg/kg sc/week), carvedilol (1 mg/kg ip/week), or the combination of the two drugs. Heart mitochondria isolated from doxorubicin-treated rats exhibited depressed rates for state 3 respiration (336 +/- 26 versus 425 +/- 53 natom O/min/mg protein) and a lower respiratory control ratio (RCR) (4.3 +/- 0.6 versus 5.8 +/- 0.4) compared with cardiac mitochondria isolated from saline-treated rats. Mitochondrial calcium-loading capacity and the activity of NADH-dehydrogenase were also suppressed in cardiac mitochondria from doxorubicin-treated rats. Doxorubicin treatment also caused a decrease in RCR for liver mitochondria (3.9 +/- 0.9 versus 5.6 +/- 0.7 for control rats) and inhibition of hepatic cytochrome oxidase activity. Coadministration of carvedilol decreased the extent of cellular vacuolization in cardiac myocytes and prevented the inhibitory effect of doxorubicin on mitochondrial respiration in both heart and liver. Carvedilol also prevented the decrease in mitochondrial Ca(2+) loading capacity and the inhibition of the respiratory complexes of heart mitochondria caused by doxorubicin. Carvedilol by itself did not affect any of the parameters measured for heart or liver mitochondria. It is concluded that this protection by carvedilol against both the structural and functional cardiac tissue damage may afford significant clinical advantage in minimizing the dose-limiting mitochondrial dysfunction and cardiomyopathy that accompanies long-term doxorubicin therapy in cancer patients.
Insights
Carvedilol, an antioxidant drug, protects against doxorubicin-induced heart and liver mitochondrial damage. This finding suggests carvedilol may reduce chemotherapy-related cardiomyopathy in cancer patients.
Area of Science:
- Biochemistry
- Cardiology
- Pharmacology
Background:
- Doxorubicin chemotherapy can cause dose-limiting, irreversible cardiomyopathy.
- Oxidative stress and mitochondrial dysfunction are implicated in doxorubicin cardiotoxicity.
- Carvedilol possesses antioxidant properties and is a nonselective beta-adrenergic receptor antagonist.
Purpose of the Study:
- To investigate if carvedilol protects against cardiac and hepatic mitochondrial dysfunction induced by doxorubicin.
- To test the hypothesis that carvedilol mitigates doxorubicin's toxic effects on cellular energy production.
Main Methods:
- Isolated heart and liver mitochondria from rats subjected to 7-week treatment with doxorubicin, carvedilol, or both.
- Assessed mitochondrial respiration rates (state 3), respiratory control ratio (RCR), calcium-loading capacity, and enzyme activities (NADH-dehydrogenase, cytochrome oxidase).
Main Results:
- Doxorubicin treatment significantly reduced state 3 respiration and RCR in heart mitochondria, and RCR in liver mitochondria.
- Doxorubicin also impaired mitochondrial calcium-loading capacity and NADH-dehydrogenase activity in the heart, and inhibited hepatic cytochrome oxidase.
- Coadministration of carvedilol prevented doxorubicin-induced mitochondrial dysfunction in both organs and reduced cardiac myocyte vacuolization.
Conclusions:
- Carvedilol effectively protects against doxorubicin-induced structural and functional damage to cardiac and hepatic mitochondria.
- Carvedilol may offer a clinical benefit in minimizing dose-limiting mitochondrial dysfunction and cardiomyopathy in cancer patients undergoing doxorubicin therapy.