TY - JOUR
T1 - Decreased cardiac activity of AMP deaminase in subjects with the AMPD1 mutation - A potential mechanism of protection in heart failure
AU - Kalsi, Kameljit K.
AU - Yuen, Ada H.Y.
AU - Rybakowska, Iwona M.
AU - Johnson, Philip H.
AU - Slominska, Ewa
AU - Birks, Emma J.
AU - Kaletha, Krystian
AU - Yacoub, Magdi H.
AU - Smolenski, Ryszard T.
N1 - Funding Information:
This study was supported by the British Heart Foundation (PG99/173) and Harefield Research Foundation.
PY - 2003/9/1
Y1 - 2003/9/1
N2 - 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.
AB - 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.
KW - Adenosine
KW - Gene expression
KW - Heart failure
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U2 - 10.1016/S0008-6363(03)00497-8
DO - 10.1016/S0008-6363(03)00497-8
M3 - Article
C2 - 14499869
AN - SCOPUS:1642299985
SN - 0008-6363
VL - 59
SP - 678
EP - 684
JO - Cardiovascular Research
JF - Cardiovascular Research
IS - 3
ER -