Adenosine A3 receptor-mediated Protection Against Doxorubicin-induced Mitochondrial Damage in Cardiac Cells

摘要

The cardiotoxicity, associated with doxorubicin (DOX) treatment, limits the therapeutic efficiency of this drug. The objective of this study was to determine whether the protection demonstrated by adenosine A_3 receptor (A_3R) activation with the selective agonist Cl-IB-MECA may protect against intramitochondrial DOX accumulation, Ca~(2+) overload and a decrease of DOX-induced cardiomyopathy in experiments in-vitro and in-vivo. Protection from DOX damage was found after treatment with 100 nM A_3R agonist Cl-IB-MECA but not with A1R agonist. DOX decreased mitochondrial membrane potential as determined by DASPMI and increased Ca~(2+) cytoplasmic and mitochondrial levels, while Cl-IB-MECA prevented these effects. Echocardiography data have shown that left ventricular end diastolic diameter (LVEDd) and left ventricular end systolic diameter (LVESd) were higher and fractional shortening (FS) was significantly smaller in DOX treated animals compared to the control groups (p<0.01). DOX combined with Cl-IB-MECA resulted in improved cardiac hemodinamic function.