Constitutive myocardial A1-adenosine receptor overexpression in mice induced dilated cardiomyopathy and death within 6 to 12 weeks, whereas delaying expression until adulthood ameliorated pathology.
Does regulated overexpression of the A1-adenosine receptor in mice cause adverse changes in cardiac morphology and function?
Robust constitutive myocardial A1-AR overexpression induces a dilated cardiomyopathy in mice, which is partially ameliorated by delaying expression until adulthood or discontinuing induction.
BACKGROUND: Both the A1- and A3-adenosine receptors (ARs) have been implicated in mediating the cardioprotective effects of adenosine. Paradoxically, overexpression of both A1-AR and A3-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 A1-AR using a cardiac-specific and tetracycline-transactivating factor-regulated promoter. METHODS AND RESULTS: Constitutive A1-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 A1-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 A1-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 A1-AR induction mitigated cardiac dysfunction and significantly improved survival rate. CONCLUSIONS: These data suggest that robust constitutive myocardial A1-AR overexpression induces a dilated cardiomyopathy, whereas delaying A1-AR expression until adulthood ameliorated but did not eliminate the development of cardiac pathology. Thus, the inducible A1-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.
Funakoshi et al. (Tue,) conducted a other in Cardiac remodeling and cardiomyopathy. Constitutive A1-adenosine receptor overexpression vs. Delayed A1-AR expression or discontinuation of induction was evaluated on Cardiac dilatation and survival. Constitutive myocardial A1-adenosine receptor overexpression in mice induced dilated cardiomyopathy and death within 6 to 12 weeks, whereas delaying expression until adulthood ameliorated pathology.