© 2005 European Society of Cardiology
An isoform shift in the cardiac adenine nucleotide translocase expression alters the kinetic properties of the carrier in dilated cardiomyopathy
a Charité University Medicine, Campus Benjamin Franklin Department of Cardiology, Berlin, Germany
b Department of Cardiothoracic and Vascular Surgery Deutsches Herzzentrum Berlin, Berlin, Germany
* Corresponding author. Charité-Campus Benjamin Franklin, Department of Cardiology and Pneumology, Hindenburgdamm 30, 12200 Berlin, Germany. Tel.: +49 30 8445 4577; fax: +49 30 8445 3565. E-mail address: andrea.doerner{at}charite.de
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Abstract |
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Background: Impaired mitochondrial ADP/ATP transport and altered adenine nucleotide translocase (ANT) isoform expression characterized by enhanced ANT1 and decreased ANT2 expression have been implicated in the pathophysiology of dilated cardiomyopathy (DCM). It is still unknown whether restricted ANT function results from exogenous factors, or mutations in the ANT genes, or whether the imbalance in the isoform composition causes the reduced ADP/ATP transport. We performed DNA mutation screening of ANT genes and analyzed the kinetic properties of ANT protein isolated from DCM hearts and controls in a reconstituted system excluding natural environmental influences.
Results: A G1409T polymorphism in ANT2 leads to an exchange from Arg111 to Leu111 in healthy blood donors (n=60) with allele frequencies of 76% and 24%. This polymorphism was neither associated with DCM (74%, 26%; n=93) nor with altered myocardial ANT isoform expression or restricted ANT function (89%, 11%; n=8). However, there was a remarkable reduction in the maximum transport activity (vmax) of reconstituted ANT from DCM hearts with altered ANT isoform expression (498±113 µmol min–1 g–1 incorporated protein vs. 1112±178 µmol min–1 g–1 incorporated protein, p<0.01). Moreover, the substrate affinity of DCM myocardial ANT to ATP was slightly reduced with an increased Km value of 104.3±2.4 µM vs. 90.4±2.9 µM in controls (p<0.03).
Conclusion: The altered isoform expression in DCM hearts entails changes in the kinetic properties of total ANT protein restricting ANT function and contributing to disturbed energy metabolism in DCM.
Key Words: Adenine nucleotide translocase • Dilated cardiomyopathy • Isoform • Mitochondrial transport
Received November 5, 2004; Revised December 8, 2004; Accepted May 5, 2005