Effects of cardiac-restricted overexpression of the A2A adenosine receptor on adriamycin-induced cardiotoxicity

Activation of the A2A adenosine receptor (A2AR) has been shown to be cardioprotective. We hypothesized that A2AR overexpression could protect the heart from adriamycin-induced cardiomyopathy. Transgenic (TG) mice overexpressing the A2AR and wild-type mice (WT) were injected with adriamycin (5 mg·kg−1·wk−1 ip, 4 wk). All WT mice survived adriamycin treatment while A2AR TG mice suffered 100% mortality at 4 wk. Telemetry showed progressive prolongation of the QT interval, bradyarrhythmias, heart block, and sudden death in adriamycin-treated A2AR TG but not WT mice. Both WT and A2AR TG demonstrated similar decreases in heart function at 3 wk after treatment. Adriamycin significantly increased end-diastolic intracellular Ca2+ concentration in A2AR TG but not in WT myocytes (P < 0.05). Compared with WT myocytes, action potential duration increased dramatically in A2AR TG myoctyes (P < 0.05) after adriamycin treatment. Expression of connexin 43 was decreased in adriamycin treated A2AR TG but not WT mice. In sharp contrast, A2AR overexpression induced after the completion of adriamycin treatment resulted in no deaths and enhanced cardiac performance compared with WT adriamycin-treated mice. Our results indicate that the timing of A2AR activation is critical in terms of exacerbating or protecting adriamycin-induced cardiotoxicity. Our data have direct relevance on the clinical use of adenosine agonists or antagonists in the treatment of patients undergoing adriamycin therapy.