Effect of AMP-Deaminase 3 Knock-Out in Mice on Enzyme Activity in Heart and Other Organs

Recent findings suggest that inhibition of AMP-deaminase (AMPD) could be effective therapeutic strategy in heart disease associated with cardiac ischemia. To establish experimental model to study protective mechanisms of AMPD inhibition we developed conditional, cardiac specific knock-outs in Cre recombinase system. AMPD3 floxed mice were crossed with Mer-Cre-Mer mice. Tamoxifen was injected to induce Cre recombinase. After two weeks, hearts, skeletal muscle, liver, kidney, and blood were collected and activities of AMPD and related enzymes were analyzed using HPLC-based procedure. We demonstrate loss of more than 90% of cardiac AMPD activity in the heart of AMPD3 -/- mice while other enzymes of nucleotide metabolism such as adenosine deaminase, purine nucleoside phosphorylase were not affected. Surprisingly, activity of AMPD was also reduced in the erythrocytes and in the kidney by 20%–30%. No change of AMPD activity was observed in the skeletal muscle and the liver.

[1]  Cheng Chi Lee,et al.  AMP Deaminase 3 Deficiency Enhanced 5′-AMP Induction of Hypometabolism , 2013, PloS one.

[2]  Jidong Cheng,et al.  AMPD3‐deficient mice exhibit increased erythrocyte ATP levels but anemia not improved due to PK deficiency , 2012, Genes to cells : devoted to molecular & cellular mechanisms.

[3]  K. Kaletha,et al.  AMP-deaminase from human preterm placenta--kinetic regulatory properties of enzyme. , 2011, Placenta.

[4]  R. Smolenski,et al.  Cardiac Muscle AMP-Deaminase from a 10-Year-Old Male Heterozygous for the AMPD1 C34T Mutation , 2010, Nucleosides, nucleotides & nucleic acids.

[5]  M. Yacoub,et al.  Pharmacological Inhibition of AMP-Deaminase in Rat Cardiac Myocytes , 2008, Nucleosides, nucleotides & nucleic acids.

[6]  N. Lamblin,et al.  The impact of the AMPD1 gene polymorphism on exercise capacity, other prognostic parameters, and survival in patients with stable congestive heart failure. A study on 686 consecutive patients. , 2006, American heart journal.

[7]  Z. Chodorowski,et al.  Full-size form of human liver AMP-deaminase? , 2004, Molecular and Cellular Biochemistry.

[8]  E. Kossowska,et al.  AMP-deaminase from human term placenta , 2003, Molecular and Cellular Biochemistry.

[9]  M. Yacoub,et al.  Decreased cardiac activity of AMP deaminase in subjects with the AMPD1 mutation--a potential mechanism of protection in heart failure. , 2003, Cardiovascular research.

[10]  M. Vasseur-Cognet,et al.  A tamoxifen‐inducible chimeric Cre recombinase specifically effective in the fetal and adult mouse liver , 2002, Hepatology.

[11]  T. Rebbeck,et al.  Common variant in AMPD1 gene predicts improved clinical outcome in patients with heart failure. , 1999, Circulation.

[12]  T. Mukai,et al.  Molecular analysis of mouse Ampd3 gene encoding heart-type isoform of AMP deaminase. , 1997, Advances in experimental medicine and biology.

[13]  K. Kaletha,et al.  AMP-deaminase from hen stomach smooth muscle--physico-chemical properties of the enzyme. , 2004, Acta biochimica Polonica.

[14]  M. Yacoub,et al.  Adenine nucleotide catabolism and adenosine formation in isolated human cardiomyocytes. , 1992, Journal of molecular and cellular cardiology.

[15]  R. Smolenski,et al.  Determination of sixteen nucleotides, nucleosides and bases using high-performance liquid chromatography and its application to the study of purine metabolism in hearts for transplantation. , 1990, Journal of chromatography.