An isoform shift in the cardiac adenine nucleotide translocase expression alters the kinetic properties of the carrier in dilated cardiomyopathy
An isoform shift in the cardiac adenine nucleotide translocase expression alters the kinetic properties of the carrier in dilated cardiomyopathy
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DOI：
10.1016/j.ejheart.2005.05.003
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发表时间：
2006-01-01
影响因子：
18.2
通讯作者：
Schultheiss, HP
中科院分区：
文献类型：
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作者：
Dörner, A;Giessen, S;Schultheiss, HP
背景：线粒体ADP/ATP转运受损和腺嘌呤核苷酸转位酶（ANT）异构体表达改变，其特征是ANT1表达增强和ANT2表达降低，与扩张型心肌病（DCM）的病理生理有关。目前尚不清楚限制的ANT功能是由外源因素引起的，还是由ANT基因突变引起的，或者是同种异构体组成的不平衡导致了ADP/ATP运输的减少。我们进行了ANT基因的DNA突变筛选，并分析了在排除自然环境影响的重建系统中从DCM心脏和对照中分离的ANT蛋白的动力学特性。结果：在健康献血者（n=60）中，ANT2基因G1409T多态性导致Arg（111）向Leu（111）交换，等位基因频率分别为76%和24%。该多态性与DCM无关（74%,26%,n = 93），也与心肌ANT异构体表达改变或ANT功能受限无关（89%,11%,n = 8）。然而，重组ANT的最大转运活性（v(max)）显著降低(498 113 mu mol min(-1) g（-1）结合蛋白vs 1112 178 mu mol min（-1) g（-1）结合蛋白，p < 0.01）。此外，DCM心肌ANT对ATP的底物亲和力略有降低，K-m值为104.3 +/- 2.4 μ M，对照组为90.4 +/- 2.9 μ M （p < 0.03）。结论：DCM心脏中同种异构体表达的改变导致了总ANT蛋白动力学特性的改变，限制了ANT功能，导致DCM能量代谢紊乱。(c) 2005年欧洲心脏病学会。Elsevier B.V.版权所有。
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 Arg(111) to Leu(111) 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 (v(max)) of reconstituted ANT from DCM hearts with altered ANT isoform expression (498 113 mu mol min(-1) g(-1) incorporated protein vs. 1112 178 mu mol 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 K-m value of 104.3 +/- 2.4 mu M vs. 90.4 +/- 2.9 gM 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. (c) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.