This Article Full Text Full Text (PDF) All Versions of this Article: 115/17/2307    most recent CIRCULATIONAHA.107.694596v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Funakoshi, H. Articles by Feldman, A. M. Search for Related Content PubMed PubMed Citation Articles by Funakoshi, H. Articles by Feldman, A. M. Related Collections Biochemistry and metabolism Congestive

(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.

---

 

CLINICAL PERSPECTIVE

This article has been cited by other articles:

				J. T. Fassett, X. Xu, X. Hu, G. Zhu, J. French, Y. Chen, and R. J. Bache Adenosine regulation of microtubule dynamics in cardiac hypertrophy Am J Physiol Heart Circ Physiol, August 1, 2009; 297(2): H523 - H532. [Abstract] [Full Text] [PDF]

				F Franceschi, J-C Deharo, R Giorgi, Y By, C Monserrat, J Condo, Z Ibrahim, A Saadjian, and R Guieu Peripheral plasma adenosine release in patients with chronic heart failure Heart, April 1, 2009; 95(8): 651 - 655. [Abstract] [Full Text] [PDF]

				X. Xu, J. Fassett, X. Hu, G. Zhu, Z. Lu, Y. Li, J. Schnermann, R. J. Bache, and Y. Chen Ecto-5'-Nucleotidase Deficiency Exacerbates Pressure-Overload-Induced Left Ventricular Hypertrophy and Dysfunction Hypertension, June 1, 2008; 51(6): 1557 - 1564. [Abstract] [Full Text] [PDF]

				B. R. DeGeorge Jr, E. Gao, M. Boucher, L. E. Vinge, J. S. Martini, P. W. Raake, J. K. Chuprun, D. M. Harris, G. W. Kim, S. Soltys, et al. Targeted Inhibition of Cardiomyocyte Gi Signaling Enhances Susceptibility to Apoptotic Cell Death in Response to Ischemic Stress Circulation, March 18, 2008; 117(11): 1378 - 1387. [Abstract] [Full Text] [PDF]