Cardiac-restricted overexpression of the A(2A)-adenosine receptor in FVB mice transiently increases contractile performance and rescues the heart failure phenotype in mice overexpressing the A(1)-adenosine receptor.
In the heart, adenosine binds to pharmacologically distinct G-protein-coupled receptors (A(1)-R, A(2A)-R, and A(3)-R). While the role of A(1)- and A(3)-Rs in the heart has been clarified, the effect of genetically manipulating the A(2A)-R has not been defined. Thus, we created mice overexpressing a cardiac-restricted A(2A)-R transgene. Mice with both low (Lo) and high (Hi) levels of A(2A)-R overexpression demonstrated an increase in cardiac contractility at 12 weeks. These changes were associated with a significantly higher systolic but not diastolic [Ca(2+)]i, higher maximal contraction amplitudes, and a significantly enhanced sarcoplasmic reticulum Ca(2+) uptake activity. At 20 weeks, the effects of A(2A)-R overexpression on cardiac contractility diminished. The positive effects elicited by A(2A)-R overexpression differ from the heart failure phenotype we observed with A(1)-R overexpression. Interestingly, coexpression of A(2A)-R TG(Hi), but not A(2A)-R TGLo, enhanced survival, prevented the development of left ventricular dysfunction and heart failure, and improved Ca(2+) handling in mice overexpressing the A(1)-R. These results suggest that adenosine-mediated signaling in the heart requires a balance between A(1)- and A(2A)-Rs--a finding that may have important implications for the ongoing clinical evaluation of adenosine receptor subtype-specific agonists and antagonists for the treatment of cardiovascular diseases.
Chan
Tung O
TO
Center For Translational Medicine, Department of Medicine, Jefferson Medical College, Philadelphia, Pennsylvania, USA.
Funakoshi
Hajime
H
Song
Jianliang
J
Zhang
Xue-Qian
XQ
Wang
JuFang
J
Chung
Paul H
PH
DeGeorge
Brent R
BR
Li
Xue
X
Zhang
Jin
J
Herrmann
David E
DE
Diamond
Maura
M
Hamad
Eman
E
Houser
Steven R
SR
Koch
Walter J
WJ
Cheung
Joseph Y
JY
Feldman
Arthur M
AM
D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism; D009202:Cardiomyopathies / Q000378:metabolism / Q000503:physiopathology; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology*; D006334:Heart Function Tests; D006439:Hemodynamics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D009928:Organ Specificity / Q000235:genetics; D010641:Phenotype; D043682:Receptor, Adenosine A1 / Q000235:genetics / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D019076:Transgenes / Q000235:genetics
D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D002118:Calcium