Open AccessCardiac‐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
Author(s) -
Chan Tung O.,
Funakoshi Hajime,
Song Jianliang,
Zhang XueQian,
Wang JuFang,
Chung Paul H.,
DeGeorge, Jr Brent R.,
Li Xue,
Zhang Jin,
Herrmann David E.,
Diamond Maura,
Hamad Eman,
Houser Steven R.,
Koch Walter J.,
Cheung Joseph Y.,
Feldman Arthur M.
Publication year - 2008
Publication title -
clinical and translational science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.303
H-Index - 44
eISSN - 1752-8062
pISSN - 1752-8054
DOI - 10.1111/j.1752-8062.2008.00027.x
Subject(s) - heart failure , contractility , adenosine , genetically modified mouse , medicine , endocrinology , adenosine receptor , transgene , diastole , receptor , contraction (grammar) , endoplasmic reticulum , biology , chemistry , microbiology and biotechnology , agonist , blood pressure , biochemistry , gene
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 clarifed, the effect of genetically manipulating the A 2A ‐R has not been defned. 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 signifcantly higher systolic but not diastolic [Ca 2+ ] i , higher maximal contraction amplitudes, and a signifcantly 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 overexpresson. 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 fnding that may have important implications for the ongoing clinical evaluation of adenosine receptor subtype‐specifc agonists and antagonists for the treatment of cardiovascular diseases.