Zlatkovic Jelena, Arrell D Kent, Kane Garvan C, Miki Takashi, Seino Susumu, Terzic Andre
Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Proteomics. 2009 Mar;9(5):1314-25. doi: 10.1002/pmic.200800718.
KCNJ11 null mutants, lacking Kir6.2 ATP-sensitive K(+) (K(ATP)) channels, exhibit a marked susceptibility towards hypertension (HTN)-induced heart failure. To gain insight into the molecular alterations induced by knockout of this metabolic sensor under hemodynamic stress, wild-type (WT) and Kir6.2 knockout (Kir6.2-KO) cardiac proteomes were profiled by comparative 2-DE and Orbitrap MS. Despite equivalent systemic HTN produced by chronic hyperaldosteronism, 114 unique proteins were altered in Kir6.2-KO compared to WT hearts. Bioinformatic analysis linked the primary biological function of the K(ATP) channel-dependent protein cohort to energetic metabolism (64% of proteins), followed by signaling infrastructure (36%) including oxidoreductases, stress-related chaperones, processes supporting protein degradation, transcription and translation, and cytostructure. Mapped protein-protein relationships authenticated the primary impact on metabolic pathways, delineating the K(ATP) channel-dependent subproteome within a nonstochastic network. Iterative systems interrogation of the proteomic web prioritized heart-specific adverse effects, i.e., "Cardiac Damage", "Cardiac Enlargement", and "Cardiac Fibrosis", exposing a predisposition for the development of cardiomyopathic traits in the hypertensive Kir6.2-KO. Validating this maladaptive forecast, phenotyping documented an aggravated myocardial contractile performance, a massive interstitial fibrosis and an exaggerated left ventricular size, all prognostic indices of poor outcome. Thus, Kir6.2 ablation engenders unfavorable proteomic remodeling in hypertensive hearts, providing a composite molecular substrate for pathologic stress-associated cardiovascular disease.
KCNJ11基因敲除突变体缺乏Kir6.2 ATP敏感性钾离子（K(ATP)）通道，对高血压（HTN）诱导的心力衰竭表现出明显的易感性。为深入了解在血流动力学应激下敲除这种代谢传感器所诱导的分子改变，通过比较二维电泳（2-DE）和轨道阱质谱（Orbitrap MS）对野生型（WT）和Kir6.2基因敲除（Kir6.2-KO）小鼠的心脏蛋白质组进行了分析。尽管慢性醛固酮增多症产生了等效的全身性高血压，但与WT心脏相比，Kir6.2-KO中有114种独特的蛋白质发生了改变。生物信息学分析将K(ATP)通道依赖性蛋白质组的主要生物学功能与能量代谢（64%的蛋白质）联系起来，其次是信号基础设施（36%），包括氧化还原酶、应激相关伴侣蛋白、支持蛋白质降解、转录和翻译的过程以及细胞结构。映射的蛋白质-蛋白质关系证实了对代谢途径的主要影响，在一个非随机网络中描绘了K(ATP)通道依赖性亚蛋白质组。对蛋白质组网络进行迭代系统研究，确定了心脏特异性的不良影响，即“心脏损伤”、“心脏扩大”和“心脏纤维化”，揭示了高血压Kir6.2-KO小鼠发生心肌病特征的易感性。对这一适应不良预测的验证表明，表型分析记录了心肌收缩性能恶化、大量间质纤维化和左心室大小过度增加，所有这些都是预后不良的指标。因此，Kir6.2基因缺失导致高血压心脏中出现不利的蛋白质组重塑，为病理应激相关的心血管疾病提供了一个复合分子基础。
