Proteomic Analysis of the Myocardium in Hypertrophic Obstructive Cardiomyopathy
Proteomic Analysis of the Myocardium in Hypertrophic Obstructive Cardiomyopathy
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DOI：
10.1161/circgen.117.001974
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发表时间：
2018-12-01
影响因子：
7.4
通讯作者：
Elliott, Perry M.
中科院分区：
文献类型：
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作者：
Coats, Caroline J.;Heywood, Wendy E.;Elliott, Perry M.
背景技术背景：肥厚型心肌病（HCM）的特点是一个复杂的表型，只有部分解释的生物学效应的个别遗传变异。本研究的目的是利用心肌组织的蛋白质组学分析，探讨后基因组phenotype.METHODS：标签-免费的蛋白质组学分析，最初比较蛋白质谱从11例肥厚型心肌病患者接受手术心肌切除术与对照样品从6个健康的未使用的供体心脏。在来自65个无关个体的心肌样本中验证了差异表达的感兴趣蛋白质（HCM [n=51]、对照组[n=7]和主动脉瓣狭窄[n=7]）通过开发和使用基于靶向多反应监测的三重四极杆质谱进行。在本研究中，共鉴定出1586个蛋白质，其中151个蛋白质在HCM中与对照组相比差异表达（P< 0.05）。蛋白质表达谱显示，在最初的发现研究中鉴定的许多蛋白质与代谢、肌肉收缩、钙调节和氧化应激相关。与对照组相比，HCM组下调的蛋白质包括肌酸激酶M型、果糖二磷酸醛缩酶A和磷酸甘油酸酯A（P< 0.001）.在HCM中上调的蛋白质包括光蛋白聚糖、碳酸酐酶3、结蛋白、α-肌动蛋白骨架和FHL 1（4.5 LIM结构域蛋白1; P< 0.01）。心肌Lumican浓度与左房面积（. 0.34，P=0.015），心脏磁共振成像上的晚期钆增强（P=0.03）和致病性肌节突变的存在（P=0.04）。结论：HCM的心肌蛋白质组提供了代谢和结构蛋白失调的支持证据。在HCM心脏中Lumican升高的发现提供了对该疾病特征性的心肌纤维化的深入了解。
BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by a complex phenotype that is only partly explained by the biological effects of individual genetic variants. The aim of this study was to use proteomic analysis of myocardial tissue to explore the postgenomic phenotype.METHODS: Label- free proteomic analysis was used initially to compare protein profiles in myocardial samples from 11 patients with HCM undergoing surgical myectomy with control samples from 6 healthy unused donor hearts. Differentially expressed proteins of interest were validated in myocardial samples from 65 unrelated individuals (HCM [n=51], controls [n=7], and aortic stenosis [n=7]) by the development and use of targeted multiple reaction monitoring- based triple quadrupole mass spectrometry.RESULTS: In this exploratory study, 1586 proteins were identified with 151 proteins differentially expressed in HCM samples compared with controls (P< 0.05). Protein expression profiling showed that many proteins identified in the initial discovery study were associated with metabolism, muscle contraction, calcium regulation, and oxidative stress. Proteins downregulated in HCM versus controls included creatine kinase M- type, fructose- bisphosphate aldolase A, and phosphoglycerate mutase (P< 0.001). Proteins upregulated in HCM included lumican, carbonic anhydrase 3, desmin, a- actin skeletal, and FHL1 (four and a half LIM domain protein 1; P< 0.01). Myocardial lumican concentration correlated with the left atrial area (.=0.34, P=0.015), late gadolinium enhancement on cardiac magnetic resonance imaging (P=0.03) and the presence of a pathogenic sarcomere mutation (P=0.04).CONCLUSIONS: The myocardial proteome of HCM provides supporting evidence for dysregulation of metabolic and structural proteins. The finding that lumican is raised in HCM hearts provides insight into the myocardial fibrosis that characterizes this disease.