Activation of A3Adenosine Receptor Protects Against Doxorubicin-induced Cardiotoxicity

Autor: Tova Zinman, Kenneth A. Jacobson, Asher Shainberg, Liaman K. Mamedova, V. Shneyvays
Rok vydání: 2001
Předmět:
Zdroj: Journal of Molecular and Cellular Cardiology. 33:1249-1261
ISSN: 0022-2828
DOI: 10.1006/jmcc.2001.1387
Popis: Adenosine exerts a marked protective effect on the heart during cardiac ischemia. This protection is mediated by binding to the A 1 and A 3 subtypes of adenosine receptor (A 1 R and A 3 R, respectively). The objective of the present study was to investigate whether activation of A 1 and A 3 adenosine receptors may reduce doxorubicin-induced damage to cardiomyocytes in culture. Cultured cardiomyocytes from newborn rats were treated with 0.5–5 μ m doxorubicin (DOX) for 18 h and then incubated in drug-free medium for an additional 24 h. This treatment resulted in cell damage and lactate dehydrogenase release, even after low (0.5 μ m) doses of the drug, and increased in a concentration-dependent manner. Activation of A 3 -subtype but not A 1 -subtype receptors attenuated doxorubicin-cardiotoxicity after drug treatment for 18 h followed by 24 h incubation in drug-free medium. Modulation of intracellular calcium mediated by activation of A 3 R, but not by A 1 R, in cultured myocytes suggested an important pathophysiological significance of this subtype of adenosine receptors. Protection by A 3 R agonist Cl-IB-MECA (2-chloro-N 6 -(3-iodobenzyl)adenosine-5′-N-methyluronamide) following DOX treatment is evident in: (1) decreases in intracellular calcium overloading and abnormalities in Ca 2+ transients; (2) reduction of free-radical generation and lipid peroxidation; (3) attenuation of mitochondrial damage by protection of the terminal link (COX-complex) of respiratory chain; (4) attenuation of the decrease in ATP production and irreversible cardiomyocyte damage. Cardioprotection caused by Cl-IB-MECA was antagonized considerably by the selective A 3 adenosine receptor antagonist MRS1523.
Databáze: OpenAIRE