Identification of biochemical adaptations in hyper- or hypocontractile hearts from phospholamban mutant mice by expression proteomics
Identification of biochemical adaptations in hyper- or hypocontractile hearts from phospholamban mutant mice by expression proteomics
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DOI：
10.1073/pnas.0308174101
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发表时间：
2004-02-24
影响因子：
11.1
通讯作者：
Emili, A
中科院分区：
文献类型：
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作者：
Pan, Y;Kislinger, T;Emili, A
受磷蛋白（PLN）是一种重要的心脏收缩调节剂，通过其结合和调节肌（内）质网Ca 2 + ATP酶的活性。为了揭示与心肌收缩力极端相关的生化适应，我们使用高通量无凝胶串联MS来监测标准微粒体组分中膜蛋白相对丰度的差异，所述标准微粒体组分分离自具有高收缩力的PLN缺失小鼠（PLN-KO）的心脏和在具有降低的收缩力的PLN缺失背景（140 A-KO）中过度表达超抑制性PLN突变体的转基因小鼠。在鉴定的782种蛋白质的一个子集中检测到显著的差异表达，包括已知的膜相关生物标志物、信号通路的组分和以前未研究的蛋白质。参与脂肪和碳水化合物代谢的蛋白质和与G蛋白信号通路相关的蛋白质激活蛋白激酶C在140 A-KO心肌中富集，而与增强收缩功能相关的蛋白质在PLN-KO突变心脏中富集。这些数据表明，Ca 2+失调，导致心肌收缩力升高或降低，诱导代偿性生化反应。
Phospholamban (PLN) is a critical regulator of cardiac contractility through its binding to and regulation of the activity of the sarco(endo)plasmic reticulum Ca2+ ATPase. To uncover biochemical adaptations associated with extremes of cardiac muscle contractility, we used high-throughput gel-free tandem MS to monitor differences in the relative abundance of membrane proteins in standard microsomal fractions isolated from the hearts of PLN-null mice (PLN-KO) with high contractility and from transgenic mice overexpressing a superinhibitory PLN mutant in a PLN-null background (140A-KO) with diminished contractility. Significant differential expression was detected for a subset of the 782 proteins identified, including known membrane-associated biomarkers, components of signaling pathways, and previously uninvestigated proteins. Proteins involved in fat and carbohydrate metabolism and proteins linked to G protein-signaling pathways activating protein kinase C were enriched in 140A-KO cardiac muscle, whereas proteins linked to enhanced contractile function were enriched in PLN-KO mutant hearts. These data demonstrate that Ca2+ dysregulation, leading to elevated or depressed cardiac contractility, induces compensatory biochemical responses.