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

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 clarified, the effect of genetically manipulating the A2A-R has not been defined. Thus, we created miceoverexpressing 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 significantly higher systolic but not diastolic [Ca2+]i, higher maximal contraction amplitudes, and a significantly 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 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.