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 Ͼ90% 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. (Circulation. 2006;114:2240-2250.)

A 1 Adenosine Receptor Upregulation Accompanies Decreasing Myocardial Adenosine Levels in Mice With Left Ventricular Dysfunction

“…39 However, overexpression of A 1 -AR diminished Ca 2ϩ transport into the sarcoplasmic reticulum, 47 increased the heart-to-bodyweight ratio, and decreased the response to catecholamines without influencing intrinsic myocardial contractility in C57Bl6 mice 11 but caused marked cardiac dilatation and dysfunction in friend virus B-type mice. 48 In addition, high levels of overexpression of the A 3 -AR led to the development of a dilated cardiomyopathy. 12 Thus, it is unclear whether the marked decrease in myocardial adenosine levels found in the TNF 1.6 mice is cardioprotective or maladaptive.…”

Signaling pathways involving adenosine A2A and A2B receptors in wound healing and fibrosis

“…This effect is mediated by phosphatidylinositol-3 (PI3) kinase and Akt kinase signaling which have been shown to play an important role in both physiologic and pathologic cardiac hypertrophies and in the regulation of cell survival [43]. Antagonism of A 1 R with the highly selective inhibitor SLV320 attenuates myocardial fibrosis and albuminuria without influencing blood pressure in a uremic cardiomyopathy model [44].…”

Targeted Inhibition of Cardiomyocyte Gi Signaling Enhances Susceptibility to Apoptotic Cell Death in Response to Ischemic Stress

“…The stable tetracycline analog doxycycline was administered to mice at 300 mg/kg of mouse diet (Bio-Serv, Frenchtown, NJ) to repress GiCT transcription as described. 25 …”