title: 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.
abstract: 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.
authors.affiliation: Center For Translational Medicine, Department of Medicine, Jefferson Medical College, Philadelphia, Pennsylvania, USA.
authors.forename: Tung O
authors.initials: TO
authors.lastname: Chan
authors.forename: Hajime
authors.initials: H
authors.lastname: Funakoshi
authors.forename: Jianliang
authors.initials: J
authors.lastname: Song
authors.forename: Xue-Qian
authors.initials: XQ
authors.lastname: Zhang
authors.forename: JuFang
authors.initials: J
authors.lastname: Wang
authors.forename: Paul H
authors.initials: PH
authors.lastname: Chung
authors.forename: Brent R
authors.initials: BR
authors.lastname: DeGeorge
authors.forename: Xue
authors.initials: X
authors.lastname: Li
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.forename: David E
authors.initials: DE
authors.lastname: Herrmann
authors.forename: Maura
authors.initials: M
authors.lastname: Diamond
authors.forename: Eman
authors.initials: E
authors.lastname: Hamad
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.forename: Joseph Y
authors.initials: JY
authors.lastname: Cheung
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Feldman
mesh_terms: 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
chemical_list: D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D002118:Calcium