Published Online
on November 6, 2006

A more recent version of this article appeared on November 21, 2006

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Submitted on February 11, 2006
Revised on September 13, 2006
Accepted on September 15, 2006

Regulated Overexpression of the A₁-Adenosine Receptor in Mice Results in Adverse but Reversible Changes in Cardiac Morphology and Function

Hajime Funakoshi MD, PhD, Tung O. Chan PhD, Julie C. Good BS, Joseph R. Libonati PhD, Jarkko Piuhola MD, PhD, Xiongwen Chen PhD, Scott M. MacDonnell PhD, Ling L. Lee MS, David E. Herrmann BS, Jin Zhang PhD, Jeffrey Martini BS, Timothy M. Palmer PhD, Atsushi Sanbe PhD, Jeffrey Robbins PhD, Steven R. Houser PhD, Walter J. Koch PhD, and Arthur M. Feldman MD, PhD^*

From the Center for Translational Medicine (H.F., T.O.C., J.C.G., L.L.L., D.E.H., J.Z., J.M., W.J.K., A.M.F.), Department of Medicine, Jefferson Medical College, Philadelphia, Pa; Cardiovascular Research Center (X.C., S.M.M., S.R.H.), Temple University School of Medicine, Philadelphia, Pa; Department of Kinesiology (J.R.L.), Temple University, Philadelphia, Pa; Department of Internal Medicine (J.P.), University of Oulu, Finland; Division of Biochemistry and Molecular Biology (T.M.P.), Institute of Biomedical and Life Sciences, University of Glasgow, Scotland; and Division of Molecular Cardiovascular Biology (A.S., J.R.), Cincinnati Children’s Hospital, Cincinnati, Ohio.

^* To whom correspondence should be addressed. E-mail: Arthur.Feldman{at}Jefferson.edu.

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.

Key words: heart failure • adenosine • cardiomyopathy • hypertrophy • myocardial contraction • remodeling • receptors

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