Proteomic profiling of KATP channel-deficient hypertensive heart maps risk for maladaptive cardiomyopathic outcome.
Proteomic profiling of KATP channel-deficient hypertensive heart maps risk for maladaptive cardiomyopathic outcome.
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KATP 通道缺陷型高血压心脏的蛋白质组学分析绘制了适应不良心肌病结果的风险。
DOI：
10.1002/pmic.200800718
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发表时间：
2009
期刊：
影响因子：
3.4
通讯作者：
Terzic,Andre
中科院分区：
文献类型：
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作者：
Zlatkovic,Jelena;Arrell,DKent;Kane,GarvanC;Miki,Takashi;Seino,Susumu;Terzic,Andre
KCNJ11null突变体缺乏Kir6.2 ATP敏感K+(KATP)通道，对高血压（HTN）诱导的心力衰竭表现出明显的易感性。为了深入了解这种代谢传感器在血流动力学应激下被敲除所引起的分子改变，野生型（WT）和Kir6.2敲除（Kir6.2‐KO）心脏蛋白质组通过对比2‐DE和Orbitrap ms进行了分析。尽管慢性高醛固酮症产生了等量的全身HTN，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KATPchannel依赖蛋白群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、支持蛋白质降解、转录和翻译以及细胞结构的过程。绘制的蛋白质关系验证了对代谢途径的主要影响，描绘了非随机网络中KATPchannel依赖的亚蛋白质组。蛋白质组学网络的迭代系统询问优先考虑心脏特异性不良反应，即。，“心脏损伤”，“心脏增大”和“心脏纤维化”，揭示了高血压Kir6.2‐KO中心肌病特征发展的易感性。为了验证这种适应性不良的预测，表型分析显示心肌收缩性能加重、间质纤维化和左心室大小增大，这些都是预后不良的预后指标。因此，Kir6.2消融在高血压心脏中产生不利的蛋白质组重塑，为病理性应激相关心血管疾病提供了复合分子底物。
KCNJ11null mutants, lacking Kir6.2 ATP‐sensitive K+(KATP) 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 KATPchannel‐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 KATPchannel‐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.