Effects of cardiac-restricted overexpression of the A(2A) adenosine receptor on adriamycin-induced cardiotoxicity.
Activation of the A(2A) adenosine receptor (A(2A)R) has been shown to be cardioprotective. We hypothesized that A(2A)R overexpression could protect the heart from adriamycin-induced cardiomyopathy. Transgenic (TG) mice overexpressing the A(2A)R 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 A(2A)R 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 A(2A)R TG but not WT mice. Both WT and A(2A)R TG demonstrated similar decreases in heart function at 3 wk after treatment. Adriamycin significantly increased end-diastolic intracellular Ca(2+) concentration in A(2A)R TG but not in WT myocytes (P < 0.05). Compared with WT myocytes, action potential duration increased dramatically in A(2A)R TG myocytes (P < 0.05) after adriamycin treatment. Expression of connexin 43 was decreased in adriamycin treated A(2A)R TG but not WT mice. In sharp contrast, A(2A)R 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 A(2A)R 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.
Hamad
Eman A
EA
Center for Translational Medicine, Dept. of Medicine, Jefferson Medical College, 1025 Walnut St, Suite 822 College, Philadelphia, PA 19107, USA.
Li
Xue
X
Song
Jianliang
J
Zhang
Xue-Qian
XQ
Myers
Valerie
V
Funakoshi
Hajime
H
Zhang
Jin
J
Wang
Jufang
J
Li
Jifen
J
Swope
David
D
Madonick
Ashley
A
Farber
John
J
Radice
Glenn L
GL
Cheung
Joseph Y
JY
Chan
Tung O
TO
Feldman
Arthur M
AM
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects; D015820:Cadherins / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000378:metabolism* / Q000401:mortality; D002478:Cells, Cultured; D018031:Connexin 43 / Q000378:metabolism; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000009:adverse effects* / Q000494:pharmacology; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D015820:Cadherins; D018031:Connexin 43; D043705:Receptor, Adenosine A2A; D004317:Doxorubicin; D002118:Calcium