© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Decreased cardiac activity of AMP deaminase in subjects with the AMPD1 mutation—A potential mechanism of protection in heart failure
aHeart Science Centre, Imperial College at Harefield Hospital, Harefield, Middlesex UB9 6JH, UK
bDepartment of Biochemistry, Medical University of Gdansk, Gdansk, Poland
r.smolenski{at}imperial.ac.uk
* Corresponding author. Tel.: +44-1895-828-829; fax: +44-1895-828-864.
Objectives: Possession of the C34T (Glu12Stop) nonsense mutation in the AMP-deaminase 1 (AMPD1) gene has been shown to be associated with improved prognosis in heart failure and ischemic heart disease. The most likely event leading to these clinical effects is a reduced capacity of the AMP deamination pathway and increased production of cardio-protective adenosine. However, since AMPD1 is predominantly expressed in skeletal muscle, the protective effects could be related not only to local cardiac changes, but also to a systemic mechanism. In the present study we evaluated the effect of the C34T mutation on cardiac AMP-deaminase activity and on the systemic changes in adenosine production. Methods: The presence of the C34T mutation was assayed by single-stranded conformational polymorphism (SSCP). Analysis of the AMPD1 genotype and measurement of enzyme activities was performed on 27 patients with heart failure (HF). In addition, blood adenosine concentration was measured by liquid chromatography/mass spectrometry (LC/MS) in 21 healthy subjects with established AMPD1 genotype at rest and following exhaustive exercise. Results: Cardiac AMP-deaminase activity in heterozygotes (C/T) was 0.59±0.02 nmol/min/g wet wt—about half of the activity found in normal wild-type (C/C) individuals (1.06±0.09 nmol/min/g wet wt, P=0.003). There were no significant differences in the activities of any other enzymes between subjects with the C/T or C/C genotype. Resting venous blood adenosine concentration was similar in subjects with C/C, C/T and homozygous for the mutated allele (T/T) genotype. Following exercise, a significant increase in adenosine was observed in T/T subjects (by 0.013±0.009 µmol/l, P=0.035) but not in C/C (0.003±0.009 µmol/l) or C/T (–0.002±0.011 µmol/l). Conclusions: Our findings indicate that the C34T mutation of AMPD1 leads to a decrease in cardiac enzyme activity of AMP-deaminase without changes in any other adenosine-regulating enzymes, highlighting the importance of local cardiac metabolic changes. Systemic (blood) changes in adenosine concentration were apparent only in homozygous subjects and therefore may play a relatively small part in cardio-protection.
KEYWORDS Adenosine; Heart failure; Gene expression
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  N. P. Riksen, B. Franke, W. J.G. Oyen, G. F. Borm, P. van den Broek, O. C. Boerman, P. Smits, and G. A. Rongen Augmented hyperaemia and reduced tissue injury in response to ischaemia in subjects with the 34C > T variant of the AMPD1 gene Eur. Heart J., May 1, 2007; 28(9): 1085 - 1091. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Paolocci, B. Tavazzi, R. Biondi, Y. A. Gluzband, A. M. Amorini, C. G. Tocchetti, M. Hejazi, P. M. Caturegli, J. Kajstura, G. Lazzarino, et al. Metalloproteinase Inhibitor Counters High-Energy Phosphate Depletion and AMP Deaminase Activity Enhancing Ventricular Diastolic Compliance in Subacute Heart Failure J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 506 - 513. [Abstract] [Full Text] [PDF]
|
|