ATP-sensitive K+ channel knockout induces cardiac proteome remodeling predictive of heart disease susceptibility.
ATP-sensitive K+ channel knockout induces cardiac proteome remodeling predictive of heart disease susceptibility.
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DOI：
10.1021/pr900561g
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发表时间：
2009-10
影响因子：
4.4
通讯作者：
Terzic, Andre
中科院分区：
文献类型：
--
作者：
Arrell, D. Kent;Zlatkovic, Jelena;Kane, Garvan C.;Yamada, Satsuki;Terzic, Andre
关键词：
预测疾病易感性需要在明显症状发作之前检测适应不良特征。一个恰当的例子是心脏ATP敏感性K+（KATP）通道病，其潜在的疾病脆弱性的底物仍有待确定。解决分子病理生物学，即使是单一的遗传缺陷，也需要一个系统平台来可靠地诊断疾病易感性。本文将高通量蛋白质组学分析与网络生物学相结合，以解码Kir6.2 KATP通道孔缺失的后果。差异二维凝胶电泳可重复地分辨来自无症状野生型和Kir6.2敲除对应物的心脏的> 800种蛋白质种类。KATP通道消融重塑心脏蛋白质组，显着改变71个蛋白质点，其中102个独特的身份被分配后的混合线性离子阱四极杆-轨道阱串联质谱。本体论注释将KATP通道依赖性蛋白质组分层为主要的生物能量模块（63个解析的身份），另外的集中集代表信号传导分子（6）、氧化还原酶（8）、伴侣蛋白（6）和参与catalysts的蛋白质（6）、细胞结构（8）以及转录和翻译（5）。蛋白质相互作用映射，结合表达水平的变化，本地化KATP通道相关的亚蛋白质组内的非随机无标度网络。KATP通道缺陷环境的全球评估证实了对代谢途径的主要影响，并揭示了与心血管疾病相关的标志物的过度表达。在Kir6.2基因敲除的实验中，分级应力的施加加重了结构和功能性心肌缺陷，降低了存活率并验证了疾病易感性的预测。因此，蛋白质组学制图提供了一个完整的视图KATP通道缺失引起的心脏分子重塑，建立一个系统的方法，预测在症状前阶段的结果。
Forecasting disease susceptibility requires detection of maladaptive signatures prior to onset of overt symptoms. A case-in-point are cardiac ATP-sensitive K+ (KATP) channelopathies, for which the substrate underlying disease vulnerability remains to be identified. Resolving molecular pathobiology, even for single genetic defects, mandates a systems platform to reliably diagnose disease predisposition. High-throughput proteomic analysis was here integrated with network biology to decode consequences of Kir6.2 KATP channel pore deletion. Differential two-dimensional gel electrophoresis reproducibly resolved > 800 protein species from hearts of asymptomatic wild-type and Kir6.2-knockout counterparts. KATP channel ablation remodeled the cardiac proteome, significantly altering 71 protein spots, from which 102 unique identities were assigned following hybrid linear ion trap quadrupole-Orbitrap tandem mass spectrometry. Ontological annotation stratified the KATP channel-dependent protein cohort into a predominant bioenergetic module (63 resolved identities), with additional focused sets representing signaling molecules (6), oxidoreductases (8), chaperones (6), and proteins involved in catabolism (6), cytostructure (8), and transcription and translation (5). Protein interaction mapping, in conjunction with expression level changes, localized a KATP channel-associated subproteome within a nonstochastic scale-free network. Global assessment of the KATP channel deficient environment verified the primary impact on metabolic pathways and revealed overrepresentation of markers associated with cardiovascular disease. Experimental imposition of graded stress precipitated exaggerated structural and functional myocardial defects in the Kir6.2-knockout, decreasing survivorship and validating the forecast of disease susceptibility. Proteomic cartography thus provides an integral view of molecular remodeling in the heart induced by KATP channel deletion, establishing a systems approach that predicts outcome at a presymptomatic stage.
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DOI：
10.1084/jem.20061916
发表时间：
2007-02-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Behfar A;Perez-Terzic C;Faustino RS;Arrell DK;Hodgson DM;Yamada S;Puceat M;Niederländer N;Alekseev AE;Zingman LV;Terzic A
通讯作者：
Terzic A
影响因子：
5.2
作者：
Arrell, D. Kent;Niederlaender, Nicolas J.;Terzic, Andre
通讯作者：
Terzic, Andre
影响因子：
4.8
作者：
Abraham, MR;Selivanov, VA;Terzic, A
通讯作者：
Terzic, A
影响因子：
4.8
作者：
Crawford, RM;Ranki, HJ;Jovanovic, A
通讯作者：
Jovanovic, A
影响因子：
20.1
作者：
Arrell, D. Kent;Elliott, Steven T.;Van Eyk, Jennifer E.
通讯作者：
Van Eyk, Jennifer E.