Regulated Overexpression of the A 1 -Adenosine Receptor in Mice Results in Adverse but Reversible Changes in Cardiac Morphology and Function

Abstract

Background— Both the A 1 - and A 3 -adenosine receptors (ARs) have been implicated in mediating the cardioprotective effects of adenosine. Paradoxically, overexpression of both A 1 -AR and A 3 -AR is associated with changes in the cardiac phenotype. To evaluate the temporal relationship between AR signaling and cardiac remodeling, we studied the effects of controlled overexpression of the A 1 -AR using a cardiac-specific and tetracycline-transactivating factor–regulated promoter. Methods and Results— Constitutive A 1 -AR overexpression caused the development of cardiac dilatation and death within 6 to 12 weeks. These mice developed diminished ventricular function and decreased heart rate. In contrast, when A 1 -AR expression was delayed until 3 weeks of age, mice remained phenotypically normal at 6 weeks, and >90% of the mice survived at 30 weeks. However, late induction of A 1 -AR still caused mild cardiomyopathy at older ages (20 weeks) and accelerated cardiac hypertrophy and the development of dilatation after pressure overload. These changes were accompanied by gene expression changes associated with cardiomyopathy and fibrosis and by decreased Akt phosphorylation. Discontinuation of A 1 -AR induction mitigated cardiac dysfunction and significantly improved survival rate. Conclusions— These data suggest that robust constitutive myocardial A 1 -AR overexpression induces a dilated cardiomyopathy, whereas delaying A 1 -AR expression until adulthood ameliorated but did not eliminate the development of cardiac pathology. Thus, the inducible A 1 -AR transgenic mouse model provides novel insights into the role of adenosine signaling in heart failure and illustrates the potentially deleterious consequences of selective versus nonselective activation of adenosine-signaling pathways in the heart.