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(Circulation. 2007;115:2307-2315.)
© 2007 American Heart Association, Inc.

Molecular Cardiology

A₁ Adenosine Receptor Upregulation Accompanies Decreasing Myocardial Adenosine Levels in Mice With Left Ventricular Dysfunction

Hajime Funakoshi, MD, PhD; Lefteris C. Zacharia, PhD; Zhonghua Tang, MD, PhD; Jin Zhang, PhD; Ling L. Lee, MS; Julie C. Good, MS; David E. Herrmann, MS; Yoshihiro Higuchi, MD, PhD; Walter J. Koch, PhD; Edwin K. Jackson, PhD; Tung O. Chan, PhD; Arthur M. Feldman, MD, PhD

From the Center for Translational Medicine, Department of Medicine, Jefferson Medical College, Philadelphia, Pa (H.F., Z.T., J.Z., L.L.L., J.C.G., D.E.H., W.J.K., T.O.C., A.M.F.); Medical Institute of Bioregulation, Kyushu University, Kyushu, Japan (Y.H.); and Center for Clinical Pharmacology, University of Pittsburgh Medical Center, Pittsburgh, Pa (L.C.Z., E.K.J.).

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

Received February 9, 2007; accepted February 23, 2007.

Background— It is well known that adenosine levels are increased during ischemia and protect the heart during ischemia/reperfusion. However, less is known about the role of adenosine–adenosine receptor (AR) pathways in hearts with left ventricular dilation and dysfunction. Therefore, we assessed adenosine levels and selective AR expression in transgenic mice with left ventricular systolic dysfunction secondary to overexpression of tumor necrosis factor- (TNF 1.6).

Methods and Results— Cardiac adenosine levels were reduced by 70% at 3 and 6 weeks of age in TNF 1.6 mice. This change was accompanied by a 4-fold increase in the levels of A₁-AR and a 50% reduction in the levels of A_2A-AR. That the increase in A₁-AR density was of physiological significance was shown by the fact that chronotropic responsiveness to the A₁-AR selective agonist 2-chloro-N⁶-cyclopentanyladenosine was enhanced in the TNF 1.6 mice. Similar changes in adenosine levels were found in 2 other models of heart failure, mice overexpressing calsequestrin and mice after chronic pressure overload, suggesting that the changes in adenosine-AR signaling were secondary to myocardial dysfunction rather than to TNF overexpression.

Conclusions— Cardiac dysfunction secondary to the overexpression of TNF is associated with marked alterations in myocardial levels of adenosine and ARs. Modulation of the myocardial adenosine system and its signaling pathways may be a novel therapeutic target in patients with heart failure.

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