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(Circulation. 2006;114:2240-2250.)
© 2006 American Heart Association, Inc.

Heart Failure

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; 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.

Correspondence to Arthur M. Feldman, MD, PhD, or Tung O. Chan, PhD, Department of Medicine, Jefferson Medical College, 1025 Walnut St, Suite 822 College, Philadelphia, PA 19107. E-mail Arthur.Feldman{at}Jefferson.edu or Tung.Chan@mail.jci.tju.edu

Received February 11, 2006; revision received September 13, 2006; accepted September 15, 2006.

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.

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