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.
Publication/Presentation Date
9-1-2008
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.
Volume
1
Issue
2
First Page
126
Last Page
133
ISSN
1752-8062
Published In/Presented At
Chan, T. O., Funakoshi, H., Song, J., Zhang, X. Q., Wang, J., Chung, P. H., DeGeorge, B. R., Jr, Li, X., Zhang, J., Herrmann, D. E., Diamond, M., Hamad, E., Houser, S. R., Koch, W. J., Cheung, J. Y., & Feldman, A. M. (2008). 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. Clinical and translational science, 1(2), 126–133. https://doi.org/10.1111/j.1752-8062.2008.00027.x
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
20354569
Department(s)
Administration and Leadership
Document Type
Article