title: A1 adenosine receptor upregulation accompanies decreasing myocardial adenosine levels in mice with left ventricular dysfunction.
abstract: 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-alpha (TNF 1.6).
  
  
  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 A2A-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.
authors: Center for Translational Medicine, Department of Medicine, Jefferson Medical College, Philadelphia, PA 19107, USA.
authors: Hajime
authors: H
authors: Funakoshi
authors: Lefteris C
authors: LC
authors: Zacharia
authors: Zhonghua
authors: Z
authors: Tang
authors: Jin
authors: J
authors: Zhang
authors: Ling L
authors: LL
authors: Lee
authors: Julie C
authors: JC
authors: Good
authors: David E
authors: DE
authors: Herrmann
authors: Yoshihiro
authors: Y
authors: Higuchi
authors: Walter J
authors: WJ
authors: Koch
authors: Edwin K
authors: EK
authors: Jackson
authors: Tung O
authors: TO
authors: Chan
authors: Arthur M
authors: AM
authors: Feldman
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000244:Adenosine Diphosphate / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D043682:Receptor, Adenosine A1 / Q000235:genetics* / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D015854:Up-Regulation / Q000502:physiology; D018487:Ventricular Dysfunction, Left / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D014409:Tumor Necrosis Factor-alpha; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D000241:Adenosine