Abstract 3861: Over-expression of the A1-Adenosine Receptor Alters Cardiac Function by Inhibiting Production of Caveolin-3
Cardiac specific constitutive over-expression of A1-adenosine receptor (A1-AR) resulted in hypertrophy, dilatation, and abnormalities in calcium handling; however the mechanisms responsible for these changes remain unclear. Caveolin-3 (Cav-3), the protein that anchors cardiac receptors in the caveolae of the cardiac T-tubule system, is crucial in A1-AR internalization, recycling and signaling. Thus, we hypothesized that the physiologic abnormalities in mice over-expressing the A1-AR (A1-AR TG) could be due to abnormalities in caveolin-3 expression. A1-AR TG mice demonstrated marked decrease in levels of cav-3 mRNA and protein when compared with WT control. Confocal microscopy demonstrated abnormal T-tubule and Caveolin-3 signal organization in A1-AR TG myocytes. Transmission electron microscopy showed areas of T-tubule dilation and focal accumulation of membranous material. These changes in Caveolin-3 expression and localization were not observed in transgenic mice with heart failure secondary to over-expression of tumor necrosis factor α (TNFα), or the A2a-adenosine receptor, and were reversed by co-overexpression of A2a-AR but not by altering the function of Gi. The changes in Caveolin-3 expression were associated with an increase in levels of nitric oxide, a well described post translational modulator of myogenin, but not changes in levels of myogenin and Id2, obligatory activator and inhibitor (respectively) of Caveolin-3 expression. Thus the heart failure phenotype of A1-AR TG mice appears to be linked, at least in part to abnormalities in Cav-3 expression and organization.