Cardiac‐Restricted Overexpression of the A2A‐Adenosine Receptor in FVB Mice Transiently Increases Contractile Performance and Rescues the Heart Failure Phenotype in Mice Overexpressing the A1‐Adenosine Receptor

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Abstract
In the heart, adenosine binds to pharmacologically distinct G-protein-coupled receptors (A1-R, A2A-R, and A3-R). While the role of A1-and A3-Rs in the heart has been clarifed, the effect of genetically manipulating the A2A-R has not been defned. Thus, we created mice overexpressing a cardiac-restricted A2A-R transgene. Mice with both low (Lo) and high (Hi) levels of A2A-R overexpression demonstrated an increase in cardiac contractility at 12 weeks. These changes were associated with a signifcantly higher systolic but not diastolic [Ca2+]i, higher maximal contraction amplitudes, and a signifcantly enhanced sarcoplasmic reticulum Ca2+ uptake activity. At 20 weeks, the effects of A2A-R overexpression on cardiac contractility diminished. The positive effects elicited by A2A-R overexpression differ from the heart failure phenotype we observed with A1-R overexpresson. Interestingly, coexpression of A2A-R TGHi, but not A2A-R TGLo, enhanced survival, prevented the development of left ventricular dysfunction and heart failure, and improved Ca2+ handling in mice overexpressing the A1-R. These results suggest that adenosine-mediated signaling in the heart requires a balance between A1- and A2A-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.

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