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

In the heart, adenosine binds to pharmacologically distinct G protein-coupled receptors (R) located on the cardiomyocyte (A1-R, A2A-R and A3-R). While the role of the A1- and A3-Rs in the heart has been clarified by selective overexpression or ablation in murine hearts, the effects of genetically manipulating the A2A-R has not been defined. 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 a marked increase in cardiac contractility at 12 weeks-of-age. These changes were associated with a significantly higher systolic but not diastolic [Ca2+]i, higher maximal contraction amplitudes, maximal shortening and re-lengthening velocities, and a significantly enhanced sarcoplasmic reticulum Ca2+ uptake activity. The alterations in Ca2+ handling were associated with an increase in the level of sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2). At 20 weeks-of-age, 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, co-expression 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 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.