Abstract 4139461: Proteomic and Phosphoproteomic Profiling in an Experimental Model of Electrical Storm

医学 仿形(计算机编程) 计算生物学 风暴 蛋白质组学 生物信息学 生物化学 生物 海洋学 基因 计算机科学 地质学 操作系统
作者
Yukiomi Tsuji,Masafumi Shimojo,Satoshi Yanagisawa,Yasuya Inden,Dobromir Dobrev,Stanley Nattel,Toyoaki Murohara
出处
期刊:Circulation [Lippincott Williams & Wilkins]
卷期号:150 (Suppl_1)
标识
DOI:10.1161/circ.150.suppl_1.4139461
摘要

Background: Electrical storm (ES), characterized by clustered ventricular tachycardia/fibrillation (VT/VF) episodes, is a major problem with substantial mortality in patients with implantable cardioverter-defibrillators (ICDs) and ischemic/non-ischemic cardiomyopathy, but available therapeutic approach is suboptimal, likely due to incomplete understanding of the pathophysiology. Objective: To identify the cardiac-specific features of protein/phosphoprotein changes in experimental ES. Methods: The model was created by inducing chronic complete atrioventricular-block in ICD-implanted rabbits, causing hypertrophy, QT prolongation, and frequent VT/VF-episodes. Relative protein/phosphoprotein abundances in hearts from 4 rabbits with ES (defined as ≥3 VF-episodes/24-hr period) experiencing 97±27 VF-episodes and 4 controls (CTL) were assessed by iTRAQ LC-MS/MS and key regulatory pathways were examined by Ingenuity-Pathway-Analysis. Results: Proteomic analysis identified 1938 proteins, 106 of which were differentially expressed between ES and CTL (False Discovery Rate (FDR)<0.1). ES was profoundly associated with mitochondrial dysfunction, oxidative phosphorylation inactivation and ATP depletion along with decreased measurement of electron transport chain and ATP synthase proteins and inner membrane-localized transporters and enzymes. Reductions in mitochondrial matrix-enzymes inferred downregulation of fatty acid β-oxidation and TCA cycle. Phosphoproteome detected 641 phosphorylated proteins, 82 of which have changes in phosphorylation state in ES versus CTL (FDR<0.1). Hyperphosphorylation of Z-disc proteins/associated proteins of sarcomeres, especially N-terminals of titin, and actin and protein kinase A subunits predicted striated muscle contraction and integrin signaling activation, which in part explain cardiac dilation with enhanced contractility due to sustained bradycardia in this model. Nuclear integrators for mitochondrial biogenesis and function, including cyclic AMP-response element binding, peroxisome proliferative activated receptor gamma, coactivator 1 alpha and nuclear respiratory factor 1, were activated, the prediction opposite to proteomic data. The activation status of other pathways linked to heart failure was undeterminable. Conclusion: ES is associated with evidence of mitochondrial dysfunction, known to contribute to ventricular dysfunction and arrhythmogenesis. Mitochondria-targeted agents merit further investigations as therapeutic targets in ES.

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