A 1 Adenosine Receptor Upregulation Accompanies Decreasing Myocardial Adenosine Levels in Mice With Left Ventricular Dysfunction failure, transgenic mice with left ventricular systolic Molecular Cardiology

Background —It is well known that adenosine levels are increased during ischemia and protect the heart during ischemia/reperfusion. However, less is known about the role of adenosine–adenosine receptor (AR) pathways in hearts with left ventricular dilation and dysfunction. Therefore, we assessed adenosine levels and selective AR expression in transgenic mice with left ventricular systolic dysfunction secondary to overexpression of tumor necrosis factor- (cid:1) (TNF 1.6). Methods and Results —Cardiac adenosine levels were reduced by 70% at 3 and 6 weeks of age in TNF 1.6 mice. This change was accompanied by a 4-fold increase in the levels of A 1 -AR and a 50% reduction in the levels of A 2A -AR. That the increase in A 1 -AR density was of physiological significance was shown by the fact that chronotropic responsiveness to the A 1 -AR selective agonist 2-chloro- N 6 -cyclopentanyladenosine was enhanced in the TNF 1.6 mice. Similar changes in adenosine levels were found in 2 other models of heart failure, mice overexpressing calsequestrin and mice after chronic pressure overload, suggesting that the changes in adenosine-AR signaling were secondary to myocardial dysfunction rather than to TNF overexpression. Conclusions —Cardiac dysfunction secondary to the overexpression of TNF is associated with marked alterations in myocardial levels of adenosine and ARs. Modulation of the myocardial adenosine system and its signaling pathways may be a novel therapeutic target in patients with heart failure. ( Circulation . 2007;115:2307-2315.) to common dogma, adenosine levels are substantially decreased in 3 different models of murine heart failure and that these changes are associated with physiologically relevant alterations in the levels of the adenosine receptor subtypes. Although these findings provide important information about the biology of adenosine-mediated receptor signaling in the heart, they also have important therapeutic implications. For example, based on the premise that adenosine levels are increased in the failing heart, ongoing clinical trials are evaluating the role of receptor-specific adenosine agonists and antagonists in the treatment of patients with heart failure. The results of the present study suggest that we need to learn more about the biological effects of adenosine to safely and effectively develop these agents.